Triterpene derivatives and remedies for liver diseases

ABSTRACT

A triterpene derivative useful for the treatment of hepatic disorders is disclosed. This compound comprises as an active ingredient a triterpene derivative represented by the following formula (IV) or a salt thereof:                    
     Y represents a single bond to form a double bond in the ring with Y bonded thereto.

CROSS-REFERENCE

This is a 371 of PCT/JP97/00555 filed Feb. 26, 1997.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to pharmaceutical compositions, forhepatic disorders, comprising triterpene derivatives or salts thereof asan active ingredient. The present invention also relates to noveltriterpene derivatives.

2. Background Art

A liver is an important organ which has various functions necessary formaintaining life of a living body, such as detoxication, variousmetabolisms, and storage of substances. It, however, often undergoesacute or chronic damage due to viruses, drugs, alcohols and othervarious causes. This induces viral hepatitis, drug-induced hepatopathy,alcoholic hepatopathy, fatty liver, and, in addition, diseases such ascirrhosis and hepatic cancer.

For treating such hepatic diseases, alimentary therapy, rest cure, andother therapies using glycyrrhizin preparations, adrenocorticalsteroids, interferon and the like have hitherto been employed. Thesetherapies, however, cannot be said to be satisfactorily effective forthe treatment of hepatic disorders. Glycyrrhizin and interferon areintravenously administered and, hence, unsuitable for prolongedadministration. Further, the interferon and steroids have a problem ofside effect.

Some triterpene derivatives have anticomplementary activity and plateletaggregation inhibitory activity. Thus, they and are known asprophylactic and pharmaceutical compositions for immunological diseasesand thrombosis (Japanese Patent Laid-Open No. 85344/1986). However,there is no report which discloses that the triterpene derivatives areeffective as a pharmaceutical composition for treating hepaticdisorders.

SUMMARY OF THE INVENTION

The present inventors have now found that certain triterpene derivativesare effective for treating hepatic disorders. Further, they havesucceeded in synthesis of novel triterpene derivatives. The presentinvention has been made based on such novel finding.

According to the first aspect of the present invention, there isprovided a pharmaceutical composition for treating a hepatic disordercomprising as an active ingredient a triterpene derivative representedby the following formula (I) or a salt thereof:

wherein

R¹ represents

a hydroxyl group,

arylmethyloxy,

lower alkoxy, or

lower alkanoyloxy;

R² represents

lower alkyl,

lower alkenyl,

—CH₂OR⁵ wherein R⁵ represents a hydrogen atom, arylmethyl, lower alkyl,or lower alkanoyl, formyl,

—COOR⁶ wherein R⁶ represents a hydrogen atom or lower alkyl, or

—CH₂N(R⁷)R⁸ wherein R⁷ and R⁸, which may be the same or different,represent a hydrogen atom, lower alkyl, aryl, or lower alkanoyl;

or R¹ and R² may combine with each other to form —O— C(R⁹)R¹⁰—C—CH₂—wherein R⁹ and R¹⁰, which may be the same or different, represent ahydrogen atom, lower alkyl, or aryl;

R³ and R⁴, which may be the same or different, represent

a hydrogen atom,

a hydroxyl group,

lower alkyl,

lower alkenyl,

aryl,

hydroxymethyl,

—N(R¹¹)R¹² wherein R¹¹ and R¹² which may be the same or different,represent a hydrogen atom, lower alkyl, or lower alkanoyl,

formyl,

—COOR⁶ wherein R⁶ is as defined above,

—OR¹³ wherein R¹³ represents lower alkyl, cyclo-lower alkyl, aralkyl,lower alkanoyl, arylcarbonyl, aralkylcarbonyl, lower alkenyl, loweralkenylcarbonyl, or aryl-lower alkenylcarbonyl;

or R³ and R⁴ may combine with each other to form oxo, hydroxyimino, oralkylidene; and

X represents O, CH₂, or NH.

According to the second aspect of the present invention, there isprovided a pharmaceutical composition for treating a hepatic disorder,comprising as an active ingredient a triterpene derivative representedby the following formula (II) or a salt thereof:

wherein

R¹⁶ represents

a hydroxyl group,

arylmethyloxy,

lower alkoxy, or

lower alkanoyloxy;

R¹⁷ represents

lower alkyl,

lower alkenyl

—CH₂₀R⁵ wherein R⁵ is as defined above, formyl,

—COOR⁶ wherein R⁶ is as defined above,

—CH₂OCON(R⁹)R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

—CON(R²⁹)R³⁰ wherein R²⁹ and R³⁰, which may be the same or different,represent a hydrogen atom, lower alkyl, lower alkanoyl, aryl, oraralkyl;

—CH₂N(R⁷)R⁸ wherein R⁷ and R⁸ are as defined above;

—C(R⁶)₂₀H wherein R⁶ is as defined above;

—COR⁶ wherein R⁶ is as defined above;

—CH═CHR⁶ wherein R⁶ is as defined above;

or R¹⁶ and R¹⁷ may combine with each other to form —O— C(R⁹)R¹⁰—O—CH₂—wherein R⁹ and R¹⁰ are as defined above;

R¹⁸ and R¹⁹, which may be the same or different, represent

a hydrogen atom,

a hydroxyl group,

arylmethyloxy,

lower alkyl,

—N(R¹¹)R¹² wherein R¹¹ and R¹² are as defined above,

—COOR⁶ wherein R⁶ is as defined above,

—OR¹³ wherein R¹³ is as defined above,

—O—(CH₂)_(m)—R²²

wherein

R²² represents

amino,

—NH—COOR²³ wherein R²³ represents arylmethyl or lower alkyl,

a hydroxyl group,

arylmethyloxy, or

—COOR²⁴ wherein R²⁴ represents a hydrogen atom, lower alkyl, orarylmethyl, and

m is an integer of 1 to 4,

—OCOCH(R²⁵)(CH₂)_(n)—R²² wherein R²² is as defined above, R²⁵ representsa hydrogen atom, lower alkyl, aralkyl, or aryl, and n is an integer of 0to 3,

—OCOCH═CH—COOR⁶ wherein R⁶ is as defined above, or —OCON(R²⁹)R³⁰ whereinR²⁹ and R³⁰ are as defined above;

or R¹⁸ and R¹⁹ may combine with each other to form oxo,

R²⁰ and R²¹ respectively represent the same meanings as R¹⁸ and R¹⁹,provided that R²⁰ and R²¹ do not represent a hydrogen atom;

or R¹⁸ and R²⁰ may combine with each other to form —O— [C(R⁹)R¹⁰]_(p)—O—wherein R⁹ and R¹⁰ are as defined above and p is an integer of 1 to 3,or —OCO[C(R⁹)R¹⁰]_(q)—OCO— wherein R⁹ and R¹⁰ are as defined above and qis an integer of 0 to 2; and

Y represents O, CH₂, NH, or a single bond to form a double bond in thering with Y bonded thereto.

According to the third aspect of the present invention, there isprovided a pharmaceutical composition for treating a hepatic disorder,comprising as an active ingredient a triterpene derivative representedby the following formula (III) or a salt thereof:

wherein

R¹, R², and Y are as defined above; and

R²⁷ represents

—O—(CH₂)_(m)—R wherein R²² and m are as defined above,

—OCOCH(R²⁵)(CH₂)_(n)—R²² wherein R²², R²⁵, and n are as defined above,

—OCON(R²⁹)R³⁰ wherein R²⁹ and R³⁰ are as defined above,

—OCO—(CH₂)n-R¹⁶ wherein R¹⁶ is as defined above, or

—OCOCH═CH—COOR⁶ wherein R⁶ is as defined above.

According to the fourth aspect of the present invention, there isprovided a pharmaceutical composition for treating a hepatic disorder,comprising as an active ingredient a triterpene derivative representedby the following formula (IV) or a salt thereof:

wherein

R¹, R R¹⁹, and Y are as defined above; and

R²⁸ represents

—CON(R²⁹)R³⁰ wherein R²⁹ and R³⁰ are as defined above,

—C(R⁶)₂OH wherein R⁶ is as defined above,

—COR^(6a) wherein R⁶a represents lower alkyl, or

—CH═CHR⁶ wherein R⁶ is as defined above.

The first group of novel compounds according to the present invention istriterpene derivatives represented by the following formula (Ia) orsalts thereof:

wherein

R¹ represents a hydroxyl group, lower alkoxy, or lower alkanoyloxy;

R² represents hydroxymethyl, lower alkoxymethyl, loweralkanoyloxymethyl, or carboxyl;

or R¹ and R² may combine with each other to form —O—C(R¹⁴)R¹⁵—O—CH₂—wherein R¹⁴ and R¹⁵, which may be the same or different, represent ahydrogen atom or lower alkyl;

R³ and R⁴, which may be the same or different, represent

a hydrogen atom,

a hydroxyl group,

lower alkyl,

lower alkenyl,

aryl,

hydroxymethyl,

—N(R¹¹)R¹² wherein R¹¹ and R¹², which may be the same or different,represent a hydrogen atom, lower alkyl, or lower alkanoyl,

formyl,

—COOR⁶ wherein R⁶ is as defined above,

—OR¹³ wherein R¹³ represents lower alkyl, cyclo-lower alkyl, aralkyl,lower alkanoyl, arylcarbonyl, aralkylcarbonyl, lower alkenyl, loweralkenylcarbonyl, or aryl-lower alkenylcarbonyl;

or R³ and R⁴ may combine with each other to form oxo, hydroxyimino, oralkylidene; and

X represents O, CH₂, or NH,

provided that compounds wherein R¹ represents a hydroxyl group, R²represents hydroxymethyl, R³ represents a hydrogen atom, R⁴ represents ahydroxyl group and X represents O are excluded.

The second group of novel compounds according to the present inventionis triterpene derivatives represented by the following formula (IIa) orsalts thereof:

wherein

R¹⁶ represents

a hydroxyl group,

arylmethyloxy,

lower alkoxy, excluding methoxy, or

lower alkanoyloxy, excluding acetoxy;

R¹⁷ represents

lower alkyl,

lower alkenyl

—CH₂OR⁵ wherein R⁵ is as defined above,

formyl,

—COOR⁶ wherein R⁶ is as defined above,

—CH₂CCON(R⁹)R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

—CON(R⁷)R⁸ wherein R⁷ and R⁸ are as defined above,

—CH₂N(R⁷)R⁸ wherein R⁷ and R⁸ are as defined above,

—C(R⁶)₂0H wherein R⁶ is as defined above,

—COR⁶a wherein R⁶a represents lower alkyl, or

—CH═CHR⁶ wherein R⁶ is as defined above;

or R¹⁶ and R¹⁷ may combine with each other to form —O—C(R⁹)R¹⁰—O—CH₂—wherein R⁹ and R¹⁰ are as defined above;

R¹⁸ and R¹⁹, which may be the same or different, represent

a hydrogen atom,

a hydroxyl group,

arylmethyloxy,

lower alkyl,

—N(R¹¹)R¹² wherein R¹¹ and R¹² are as defined above,

—COOR⁶ wherein R⁶ is as defined above,

—OR¹³ wherein R¹³ is as defined above,

—O—(CH₂)_(m)—R²²

wherein

R²² represents

amino,

—NH—COOR²³ wherein R²³ represents arylmethyl or lower alkyl,

a hydroxyl group,

arylmethyloxy, or

—COOR²⁴ wherein R²⁴ represents a hydrogen atom, lower alkyl, orarylmethyl, and

m is an integer of 1 to 4,

—OCOCH(R²⁵)(CH₂)_(n)—R²² wherein R²² is as defined above, R²⁵ representsa hydrogen atom, lower alkyl, aralkyl, or aryl, and n is an integer of 0to 3,

—OCOCH═CH—COOR⁶ wherein R⁶ is as defined above, or —OCON(R²⁹)R³⁰ whereinR²⁹ and R³⁰ are as defined above;

or R¹⁸ and R¹⁹ may combine with each other to form oxo,

R²⁰ and R²¹ respectively represent the same meanings as R¹⁸ and R¹⁹,provided that R²⁰ and R²¹ do not represent a hydrogen atom;

or R¹⁸ and R²⁰ may combine with each other to form —O—[C(R⁹)R¹⁰]_(p)—O—wherein R⁹ and R¹⁰ are as defined above and p is an integer of 1 to 3,or —OCO—[C(R⁹)R¹⁰]_(q)—OCO— wherein R⁹ and R¹⁰ are as defined above andq is an integer of 0 to 2; and

Y represents O, CH₂, NH, or a single bond to form a double bond in thering with Y bonded thereto;

provided that compounds wherein R¹⁶ represents a hydroxyl group, R¹⁷represents —CH₂OCH₃,R²⁰ represents a hydroxyl group or methoxy, both R¹⁸and R²¹ represent a hydrogen atom, R¹⁹ represents a hydroxyl group ormethoxy and Y represents a single bond, and compounds wherein R¹⁶represents a hydroxyl group, R¹⁷ represents —CH₂OH, R²⁰ represents ahydroxyl group, R¹⁸, R¹⁹, and R²¹ represent a hydrogen atom and Yrepresents a single bond are excluded.

The third group of novel compounds according to the present invention iscompounds represented by the formula (III).

The fourth group of novel compounds according to the present inventionis compounds represented by the formula (IV).

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a diagram showing the effect of the pharmaceutical compositionfor treating a hepatic disorder according to the present invention onhepatitis induced by concanavalin A in mice. Specifically, the alanineaminotransferase (ALT) activity, in plasma, which is an index ofhepatopathy was 2068±518 (u/l) for the control group, whereas, for thegroup of mice which have been treated with the pharmaceuticalcomposition for treating a hepatic disorder according to the presentinvention, it was lowered to 55±16 (u/l) which was the same level as forthe untreated group (that is, normal value).

DETAILED DESCRIPTION OF THE INVENTION

Definition

As used herein, the term “lower alkyl” as a group or a part of a groupmeans both straight and branched lower alkyls which preferably have 1 to6 carbon atoms, more preferably 1 to 4 carbon atoms. The terms “loweralkenyl” and “lower alkynyl” as a group or a part of a group mean bothstraight and branched lower alkenyls and lower alkynyls which preferablyhave 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. The term“halogen atom” means a fluorine, chlorine, bromine, or iodine atom. Theterm “aryl” preferably means phenyl, naphthyl, tolyl, methoxyphenyl orthe like. The term “aralkyl” as a group or a part of a group preferablymeans phenyl C₁₋₄ alkyl, more preferably benzyl, phenethyl or the like.

In the compounds of the present invention, examples of the arylmethyloxyinclude phenylmethyloxy and naphthylmethyloxy.

Examples of the lower alkoxy include straight or branched alkoxys having1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, tert-butoxy, pentyloxy, and hexyloxy.

Examples of the lower alkanoyloxy include straight alkanoyloxys having 2to 6 carbon atoms, such as acetoxy, propionyloxy, butyryloxy,pentanoyloxy, and hexanoyloxy.

Examples of the lower alkanoyl include straight or branched alkanoylshaving 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl,isobutyl, pentanoyl, tert-butylcarbonyl, and hexanoyl.

Examples of the lower alkyl include straight or branched alkyls having 1to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, pentyl and hexyl.

Examples of the lower alkenyl include straight or branched alkenylshaving 2 to 6 carbon atoms, such as vinyl, allyl, 2-butenyl, 3-butenyl,1-methylallyl, 2-pentenyl, and 2-hexenyl.

Examples of the aryl include phenyl, naphthyl, and biphenyl.

Examples of the cyclo-lower alkyl include cyclopropyl, cyclopentyl, andcyclohexyl. Examples of the aralkyl include benzyl, phenetyl, andphenylpropyl.

Examples of the arylcarbonyl include benzoyl and naphthylcarbonyl.

Examples of the lower alkenylcarbonyl include straight alkenylcarbonylshaving 3 to 6 carbon atoms, such as acryloyl, allylcarbonyl, and2-butenylcarbonyl.

Examples of the aralkylcarbony include phenylacetyl, phenylpropionyl,and naphthylacetyl. Examples of the aralkenylcarbonyl include cinnamoyland phenylbutenoyl.

Examples of the alkylidene include ethylidene, propylidene, andbutylidene.

For the arylmethyloxy, aryl, aralkyl, arylcarbonyl, aralkylcarbonyl, andaralkenylcarbonyl, at least one hydrogen atom thereon may be substitutedwith the number of substituents being preferably 1 to 2, and examples ofthe substituent include methyl, ethyl, methoxy, ethoxy, a halogen atom,amino, dimethylamino, a hydroxyl group, acetoxy, and methylenedioxy.

Pharmaceutical composition for treating hepatic disorders/compounds offormula (I), (II), (III), and (IV)

The compounds represented by the general formula (I), (II), (III), or(IV) and salts thereof are effective for the treatment of hepaticdisorders. Hepatic disorders, to which the compounds represented by thegeneral formula (I), (II), (III), or (IV) and salts thereof can beapplied, include acute and chronic viral hepatitis, autoimmunehepatitis, and drug-induced, toxic, alcoholic, intrahepatic cholestasis,and inborn metabolic error hepatopathy. The term “hepatopathy” usedherein refers to inflammatory hepatic disorders and, depending upon theprogress of symptom, is used as a concept embracing also fatty liver,cirrhosis, and hepatoma.

Specifically, the triterpene derivatives represented by the formula (I),(II), (III), or (IV) and salts thereof, when incubated together withhuman hepatoma cells (Hep G2) in the presence of aflatoxin B₁(hepatopathy-inducing substance), have an inhibitory activity againstnecrosis of such cells and an inhibitory activity against hepaticdisorders in concanavalin A hepatitis virus mice.

The compounds represented by the formula (I), (II), (III), or (IV) havevarious isomers, and the present invention embraces such isomers andmixtures thereof. Further, the presence of isomers attributable to othergroup(s) in the formula (I), (II), (III), or (IV) is also considered,and these isomers and mixtures thereof are also embraced in the presentinvention.

According to a preferred embodiment of the present invention, preferredcompounds represented by the formula (I), (II), (III), or (IV) have aconfiguration represented by the following formula (I-1), (II-1),(III-1), or (IV-1):

Among the compounds represented by the formula (I), (II), (III), or (IV)according to the present invention, the following groups of compoundsare preferred.

For the compounds represented by the formula (I), preferred are:

a group of compounds wherein R¹ represents a hydroxyl group, R³represents a hydrogen atom and X represents O; and

a group of compounds wherein R¹ represents a hydroxyl group, R²represents hydroxymethyl, R³ represents a hydrogen atom, R⁴ represents ahydroxyl group or —OR¹³ and X represents O.

For the compounds represented by the formula (II), preferred are:

a group of compounds wherein R¹⁶ represents a hydroxyl group, R¹⁷represents —CH₂OH, both R¹⁸ and R²⁰ represent a hydrogen atom, both R¹⁹and R²¹ represent a hydroxyl group and Y represents a single bond toform a double bond in the ring with Y bonded thereto;

a group of compounds wherein R¹⁶ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R¹⁷ represents —CH₂OR⁵, R¹⁸ represents ahydrogen atom, R¹⁹ represent —OR¹³, R²⁰ represents a hydrogen atom, R²¹represents —OR¹³ and Y represents a single bond to form a double bond inthe ring with Y bonded thereto;

a group of compounds wherein R¹⁶ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R¹⁷ represents —CH₂OR⁵, R¹⁸ and R¹⁹combine with each other to form oxo, R²⁰ and R²¹ combine with each otherto form oxo and Y represents a single bond to form a double bond in thering with Y bonded thereto;

a group of compounds wherein R¹⁶ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R¹⁷ represents —CH₂OR⁵, R¹⁸ and R¹⁹combine with each other to form oxo, R²⁰ represents a hydrogen atom, R²¹represents a hydroxyl group and Y represents a single bond to form adouble bond in the ring with Y bonded thereto;

a group of compounds wherein R¹⁶ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R¹⁷ represents —CH₂OR⁵, R¹⁸ and R¹⁹represent a hydrogen atom, R²⁰ and R²¹ combine with each other to formoxo and Y represents a single bond to form a double bond in the ringwith Y bonded thereto;

a group of compounds wherein R¹⁶ represents a hydroxyl group, loweralkoxy, excluding methoxy, or lower alkanoyloxy, excluding acetoxy, R¹⁷represents —CH₂OR⁵, R¹⁸ and R¹⁹ represent a hydrogen atom, R²⁰represents a hydrogen atom, R²¹ represents a hydroxyl group and Yrepresents a single bond to form a double bond in the ring with Y bondedthereto;

a group of compounds wherein R¹⁶ represents a hydroxyl group, R¹⁷represents —CH₂OR⁵, R¹⁸ represents a hydrogen atom, R¹⁹ represents ahydroxyl group or —OR¹³, R²⁰ represents a hydrogen atom, R²¹ representsa hydroxyl group or —OR¹³ and Y represents a single bond and, thus,represents O;

a group of compounds wherein R¹⁶ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R¹⁷ represents —C(R⁶)₂OH, R¹⁸ represents ahydrogen atom, R¹⁹ represents a hydroxyl group or —OR¹³, R²⁰ representsa hydrogen atom, R²¹ represents a hydroxyl group or —OR¹³ and Yrepresents a single bond to form a double bond in the ring with Y bondedthereto;

a group of compounds wherein R¹⁶ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R¹⁷ represents —COR^(6a), R¹⁸ represents ahydrogen atom, R¹⁹ represents a hydroxyl group or —OR¹³, R²⁰ representsa hydrogen atom, R²¹ represents a hydroxyl group or -OR¹³ and Yrepresents a single bond to form a double bond in the ring with Y bondedthereto; and

a group of compounds wherein R¹⁶ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R¹⁷ represents —CH═CHR⁶, R¹⁸ represents ahydrogen atom, R¹⁹ represents a hydroxyl group or —OR¹³, R²⁰ representsa hydrogen atom, R²¹ represents a hydroxyl group or —OR¹³ and Yrepresents a single bond to form a double bond in the ring with Y bondedthereto.

For the compounds represented by the formula (III), preferred are:

a group of compounds wherein R¹ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R² represents —CH₂OR⁵, R²⁷ represents—OCO—(CH₂)_(n)—R¹⁶ and Y represents a single bond to form a double bondin the ring with Y bonded thereto;

a group of compounds wherein R¹ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R² represents —CH₂OR⁵, R²⁷ represents—O—(CH₂)_(m)—R²² and Y represents a single bond to form a double bond inthe ring with Y bonded thereto;

a group of compounds wherein R¹ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R² represents —CH₂OR⁵, R²⁷ represents—OCOCH(R²⁵)(CH₂)_(n)—R²² or —OCOCH═CH—COOR⁶ and Y represents a singlebond to form a double bond in the ring with Y bonded thereto; and

a group of compounds wherein R¹ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R² represents —CH₂OR⁵, R²⁷ represents—OCON(R²⁹)R³⁰ and Y represents a single bond to form a double bond inthe ring with Y bonded thereto.

For the compounds represented by the formula (IV), preferred are:

a group of compounds wherein R¹⁸ and R¹⁹ represent a hydrogen atom, ahydroxyl group, or —OR¹³, R²⁸ represents —CON(R²⁹)R³⁰ wherein R²⁹ andR³⁰ are as defined above, —C(R⁶)₂OH wherein R⁶ is as defined above,-COR^(6a) wherein R^(6a) is as defined above, or —CH═CHR⁶ wherein R⁶ isas defined above.

The compounds represented by the formula (I), (II), (III), or (IV)according to the present invention may be present in the form of a salt.The salt may be formed by simply reacting the above compounds with apharmaceutically acceptable base according to a conventional method. Inthis case, inorganic bases, such as sodium hydroxide, potassiumhydroxide, aluminum hydroxide, sodium carbonate, potassium carbonate,and sodium hydrogencarbonate, and organic bases, such as piperazine,morpholine, piperidine, ethylamine, and trimethylamine, may be used asthe base.

Although the compound according to the present invention may beadministered as a raw material, it may be preferably administered as apharmaceutical composition. Pharmaceutical compositions, aspharmaceutical compositions for hepatic disorders, comprising as anactive ingredient the compound or salts thereof according to the presentinvention can be administered either orally or parenterally (e.g.,intravenous injection, intramuscular injection, subcutaneousadministration, rectal administration, or percutaneous administration)to humans or animals other than humans.

Therefore, the pharmaceutical compositions for hepatic disordersaccording to the present invention may be made into a preparationsuitable for the route of administration. Specifically, it may be mainlymade into any of the following preparations: an injection such asintravenous or intramuscular injection; an oral preparation such as acapsule, a tablet, a granule, a powder, a pill, fine subtilaes, or atroche; a preparation for rectal administration; an oleaginoussuppository; and an aqueous suppository. The above-described variouspreparations can be prepared by a conventional method using anexcipient, a filler, a binder, a wetting agent, a disintegrating agent,a surface active agent, a lubricant, a dispersing agent, a buffer, apreservative, a solubilizer, an antiseptic, a flavor, a soothing agent,a stabilizer and the like. Examples of the above additives which arenontoxic and employable in the preparations include milk sugar, fruitsugar, grape sugar, starch, gelatin, magnesium carbonate, syntheticmagnesium silicate, talc, magnesium stearate, methyl cellulose,carboxymethyl cellulose or a salt thereof, gum arabic, polyethyleneglycol, syrup, vaseline, glycerin, ethanol, propylene glycol, citricacid, sodium chloride, sodium sulfite and sodium phosphate.

The dosage of the compound represented by the formula (I) may varydepending upon the age, weight, conditions, or severity of the diseaseof a patient. In general, however, it is approximately 0.1 to 1000 mg,preferably 1 to 100 mg per day for adult human, once or twice a day. Theadministration may be made either orally or parenterally.

Group of novel compounds/compounds of formula (Ia), (IIa), (III), and(IV)

According to another aspect of the present invention, there are providednovel triterpene derivatives represented by the formula (Ia), (IIa),(III), or (IV).

Preferred examples of each group in these formulae may be the same asthose described above in connection with the formulae (I), (II), (III),and (IV).

In the above definition of the formula (IIa), for R¹⁶, methoxy wasexcluded from the lower alkoxy and acetoxy was excluded from the loweralkanoyloxy. Regarding the following groups of compounds, however,methoxy is embraced in the lower alkoxy represented by R¹⁶ and acetoxyis embraced in the lower alkanoyloxy represented by R¹⁶. Specifically,such groups of compounds are:

a group of compounds wherein R¹⁶ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R¹⁷ represents —CH₂R⁵, R¹⁸ represents ahydrogen atom, R¹⁹ represents —OR¹³, CR²⁰ represents a hydrogen atom,R²¹ represents —OR¹³ and Y represents a single bond to form a doublebond in the ring with Y bonded thereto;

a group of compounds wherein R¹⁶ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R¹⁷ represents —CH₂OR⁵, R¹⁸ and R¹⁹combine with each other to form oxo, R²⁰ and R²¹ combine with each otherto form oxo and Y represents a single bond to form a double bond in thering with Y bonded thereto;

a group of compounds wherein R¹⁶ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R¹⁷ represents —CH₂OR⁵, R¹⁸ and R¹⁹combine with each other to form oxo, R²⁰ represents a hydrogen atom, R²¹represents a hydroxyl group and Y represents a single bond to form adouble bond in the ring with Y bonded thereto; and

a group of compounds wherein R¹⁶ represents a hydroxyl group, loweralkoxy, or lower alkanoyloxy, R¹⁷ represents —CH₂OR⁵, R¹⁸ and R¹⁹represents a hydrogen atom, R²⁰ and R²¹ combine with each other to formoxo and Y represents a single bond to form a double bond in the ringwith Y bonded thereto.

For these novel compounds, preferred groups of compounds represented bythe formulae (I), (II), (III), and (IV) and preferred configurationthereof may be the same as described above in connection with the aboveformulae (I), (II), (III), and (IV).

The compounds represented by the formulae (Ia), (IIa), (III), or (IV)also have various isomers, and the present invention embraces all ofsuch isomers and mixtures thereof. Further, the presence of isomersattributable to other group(s) in the formula (Ia), (IIa), (III), or(IV) is also considered, and these isomers and mixtures thereof are alsoembraced in the present invention. The compounds represented by theformulae (Ia), (IIa), (III), or (IV) also may be easily converted to thecorresponding salts by allowing a pharmaceutically acceptable base toact on the compounds. Preferred bases may be the same as those describedabove in connection with the formulae (I), (II), (III), and (IV).

Preparation of compounds

Process (A)

Among the compounds represented by the formula (I), the compoundrepresented by the formula (VI), wherein R¹, R², R³ and R⁴ are asdefined above, may be prepared by reacting a compound represented by thefollowing formula (V), wherein R¹, R², R³ and R⁴ are as defined above,with a suitable oxidizing agent.

Solvents usable in this reaction include, for example, dichloromethane,chloroform, benzene, and toluene. Oxidizing agents usable hereininclude, for example, perbenzoic acid, m-chloroperbenzoic acid, andperacetic acid. In general, the oxidizing agent is used in an amount of1 to 3 equivalents based on the compound represented by the formula (V).The reaction may be usually carried out at 0 to 60° C.

Process (B)

Among the triterpene derivatives represented by the formula (I), thecompound represented by the following formula (VII), wherein R¹, R², R³and R⁴ are as defined above, may be prepared by reacting a compoundrepresented by the following formula (V) with a cyclopropanating agent.

Solvents usable herein include benzene, toluene, hexane, diethyl ether,tetrahydrofuran, and 1,2-dichloroethane. Cyclopropanating agents usableherein include Zn(Cu)—CH₂I₂ and Et₂Zn—CH₂I₂. In general, thecyclopropanating agent is used in an amount of 1 to 10 equivalents basedon the compound represented by the formula (V). The reaction may beusually carried out at −40 to 60° C. The addition of a Lewis acid, suchas titanium tetrachloride, to this reaction system often accelerates thereaction.

Process (C)

Among the compounds represented by the formula (I), the compoundrepresented by the formula (VIII), wherein R¹, R², R³ and R⁴ are asdefined above, may be prepared by reacting the compound represented bythe formula (V) with IN₃ and subsequently with a suitable reducingagent.

In general, IN₃ is used in an amount of 1 to 3 equivalents based on thecompound represented by the formula (V). Solvents usable in thisreaction include DMF and acetonitrile. The reaction may be carried outat 0 to 40° C. Lithium aluminum hydride may be used as the reducingagent in an amount of 1 to 5 equivalents, and solvents usable in thisreaction with the reducing agents include diethyl ether andtetrahydrofuran. The reaction with the reducing agent may be carried outat 0 to 60° C.

Process (D)

Among the compounds represented by the formula (II), the compoundrepresented by the formula (X), wherein R¹⁸, R¹⁹, R²⁰ and R²¹ are asdefined above, may be prepared by reacting a compound represented by thefollowing formula (IX), wherein R¹⁸, R⁹, R²⁰ and R²¹ are as definedabove, with a suitable oxidizing agent.

Solvents usable in this reaction include, for example, dichloromethane,chloroform, benzene, and toluene. Oxidizing agents usable hereininclude, for example, perbenzoic acid, m-chloroperbenzoic acid, andperacetic acid. In general, the oxidizing agent is used in an amount of1 to 3 equivalents based on the compound represented by the formula (V).The reaction may be usually carried out at 0 to 60° C.

Process (E)

Among the compounds represented by the formula (III), the compoundrepresented by the formula (XIV), wherein R^(27*) represents—O—(CH₂)_(m)—R²², —OCOCH(R²⁵)(CH₂)_(n)—R²², —OCON(R²⁹)R³⁰,—OCO—(CH₂)_(n)—R¹, or —OCOCH═CH—COOR⁶, and R¹⁶, R²², R²⁵, R²⁹, R³⁰, nand m are as defined above, can be prepared by the following reaction.

At the outset, a compound represented by the formula (XI), wherein R⁹and R¹⁰ are as defined above, is reacted with a compound represented bythe formula —Z—(CH₂)_(m)—R²², wherein Z represents a halogen atom,Cl—COCH(R²⁵)(CH₂)_(n)—R²², R²⁹—NCO, Cl—CO—(CH₂)_(n)—R⁶, orCl—COCH═CH—COCR⁶ in the presence or absence of a base to give a compoundrepresented by the formula (XIII) wherein R⁹, R¹⁰, R²⁷ and m are asdefined above. Solvents usable herein include diethyl ether,tetrahydrofuran, benzene, toluene, dichloromethane, chloroform, ordimethylformamide. Bases usable herein include, for example,triethylamine, pyridine, 4-dimethylaminopyridine, sodium hydride,potassium hydride, n-butyllithium, NaCH₂SOCH₃, and tert-BuOK. Thecompound represented by the formula —Z—(CH₂)_(m)—R²², wherein Zrepresents a halogen atom, Cl—COCH(R²⁵)(CH₂)—R²², R²⁹—NCO,Cl—CO—(CH₂)_(n)—R¹⁶, or Cl—COCH═CH—COOR⁶ may be used in an amount of 1to 3 equivalents based on the compound represented by the formula (XI).

The base may be usually used in an amount of 1 to 10 equivalents basedon the compound represented by the formula (XI) and, in some cases, maybe used as a solvent.

The reaction may be carried out at −60 to 60° C. The base may be usuallyused in an amount of 1 to 10 equivalents based on the compoundrepresented by the formula (XI) and, in some cases, may be used as asolvent. The reaction may be carried out at −20 to 60° C.

The compound represented by the formula (XIII) may be hydrolyzed in thepresence of an acid to prepare the compound represented by the formula(XIV). Solvents usable herein include methanol, ethanol, propanol,water, dichloromethane, and chloroform. Acids usable herein includemineral acids, such as hydrochloric acid and sulfuric acid, and Lewisacids, such as BF₃.Et₂O. In general, the reaction may be carried out at0 to 120° C.

Process (F)

Among the compounds represented by the formula (IV), the compoundrepresented by the formula (XVIII) can be prepared by the followingprocess.

At the outset, a compound represented by the formula (XV), wherein Arrepresents aryl, is reacted with a compound represented by the formula(XVI), wherein R²⁹ and R³⁰ are as defined above, in the presence of asuitable condensing agent to give a compound represented by the formula(XVII), wherein Ar, R²⁹ and R³⁰ are as defined above. Solvents usableherein include, for example, dichloromethane, chloroform, benzene,toluene, tetrahydrofuran, and diemthylformamide. Condensing agentsusable herein include dicyclohexylcarbodiimide (DCC),DCC-hydroxybenzotriazole,benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent), and diphenylphosphorylazide. The condensing agent may beused in an amount of 1 to 3 equivalents based on the compoundrepresented by the formula (XV). In general, the reaction may be carriedout at −20 to 60° C.

The compound represented by the formula (XVII) may be catalyticallyreduced in the presence of a catalyst to prepare the compoundrepresented by the formula (XVIII). Solvent usable herein include, forexample, water, methanol, ethanol, tetrahydrofuran, dioxane,dichloromethane, and chloroform. Catalysts usable herein include, forexample, Pd—C, Pd-black, and Pd(OH)₂—C. The catalyst may be used in anamount of 0.1 to 0.6 equivalent based on the compound represented by theformula (XVII). In general, the reaction may be carried out at roomtemperature in a hydrogen atmosphere of 1 to 4 atm.

The hydroxyl group of the compound represented by the formula (XVII) maybe further modified to give the compound represented by the formula(IV).

The compound represented by the formula (XV) may be prepared by thefollowing process.

A compound represented by the formula (XVa) may be reacted with acompound represented by the formula (XVb) in the presence of a base,followed by deprotection of the triaryl group to give a compoundrepresented by the formula (XVc) wherein Ar represents aryl group.Solvents usable herein include diethyl ether, THF, DMF,dimethylsulfoxide (DMSO), benzene, and toluene. Bases usable hereininclude, for example, sodium hydride, potassium hydride, n-butyllithium,NaCH₂SOCH₃, and tert-BuOK. Preferably, the base and the compoundrepresented by the formula (XVb) are used in an amount of 1 to 10equivalents based on the compound represented by the formula (XVa).Preferably, the reaction is carried out at −78 to 60° C. Thedeprotection may be carried out in the presence of a mineral acid, suchas hydrochloric acid or sulfuric acid, in a solvent, such as methanol,ethanol, isopropyl alcohol (IPA), or water, at a temperature of 0 to 80°C.

The compound represented by the formula (XVc) may be then oxidized witha suitable oxidizing agent to give a compound represented by the formula(XVd). Oxidizing agents usable herein include, for example, pyridiniumchromate, pyridinium dichromate, manganese dioxide, and DMSO oxidizingreagents, such as DMSO-oxalyl chloride. Solvents usable in this reactioninclude dichloromethane, chloroform, diethyl ether, and THF. Preferably,the oxidizing agent is used in an amount of 1 to 5 equivalents based onthe compound represented by the formula (XVc). The reaction may beusually carried out at −78 to 40° C.

The compound represented by the formula (XVd) may be further oxidizedwith a suitable oxidizing agent to prepare the compound represented bythe formula (Xv). Solvents usable herein include, for example, DMF,tert-butanol, acetone, and water. Oxidizing agents usable hereininclude, pyridinium dichromate, Jones reagent, potassium permanganate,and sodium chlorite. The oxidizing agent may be used in an amount of 1to 30 equivalents based on the compound represented by the formula(XVd). The reaction may be carried out at 0 to 60° C.

Process (G)

The compound represented by the formula (I), wherein R¹ represents loweralkoxy or lower alkanoyloxy and R² represents —CH₂OR⁵ (wherein R⁵represents lower alkyl or lower alkanoyl), the compound represented bythe formula II, wherein R¹⁶ represents arylmethyloxy, lower alkoxy, orlower alkanoyloxy and R¹⁷ represents —CH₂OR⁵ (wherein R⁵ representslower alkyl or lower alkanoyl), and the compound represented by theformula (III), wherein R¹ represents lower alkoxy or lower alkanoyloxy,and R² represents —CH₂OR⁵ (wherein R⁵ represents lower alkyl or loweralkanoyl, may be prepared by reacting respectively the compoundrepresented by the formula (I), wherein R¹ represents a hydroxyl groupand R² represents —CH₂OH, the compound represented by the formula (II),wherein R¹⁶ represents a hydroxyl group and R¹⁷ represents —CH₂OH, andthe compound represented by the formula (III), wherein R¹ represents ahydroxyl group and R² represents —CH₂OH, with a compound represented bythe formula R⁵Z or (R^(5a))₂O, wherein R represents lower alkyl or loweralkanoyl, in the presence of a base. Solvents usable in this reactioninclude diethyl ether, tetrahydrofuran, benzene, toluene,dichloromethane, chloroform, and dimethylformamide. Bases usable hereininclude, for example, triethylamine, pyridine, and4-dimethylaminopyridine. Preferably, the compound represented by theformula RSZ or (R^(5a))₂O is used in an amount of 1 to 3 equivalentsbased on the compounds represented by the formulae (I), (II), and (III).The base is used in an amount of preferably 1 to 10 equivalents based onthe compounds represented by the formulae (I), (II), and (III) and, insome cases, may be used as a solvent. The reaction may be carried out at−20 to 60° C.

Process (H)

Among the compounds represented by the formula (II), the compoundrepresented by the formula (XIX), wherein R* represents —OR¹³,—O—(CH₂)_(m)—R²², OCOCH(R²⁵)(CH₂)_(n)—R²², OCOCH═CH—COOR⁶, or—OCON(R²⁹)R³⁰, may be prepared by the following reaction.

At the outset, a compound represented by the formula (XX) may be reactedwith a compound represented by the formula R¹³Z, wherein Z represents ahalogen atom, (R¹³)₂O, Cl—COCH(R²⁵)(CH₂)_(n)—R²², Cl—COCH═CH—COOR⁶, orR²⁹—NCO, in the presence of a base to give the compound represented bythe formula (XIX). Solvents usable in this reaction include, forexample, diethyl ether, tetrahydrofuran, benzene, toluene,dichloromethane, chloroform, and dimethylformamide. Bases usable hereininclude, for example, triethylamine, pyridine, and4-dimethylaminopyridine. The compound represented by the formula R¹³Z,wherein Z represents a halogen atom, (R¹³)₂O, Cl—COCH(R²⁵)(CH₂)_(n)—R²²,R²⁹—NCO, Cl—CO—(CH₂)_(n)—R¹⁶, or Cl—COCH═CH—COOR⁶ is used in an amountof 1 to 3 equivalents based on the compound represented by the formula(Xx). In general, the base is used in an amount of 1 to 10 equivalentsbased on the compound represented by the formula (XX) and, in somecases, used as a solvent. The reaction may be carried out at −60 to 60°C.

Among the compounds represented by the formula (II), the compoundrepresented by the formula (XIX), wherein R* represents —OR¹³ or—O—(CH₂)_(m)—R²², may be prepared by reacting a compound represented bythe formula (II), wherein R¹⁸ represents a hydrogen atom, R¹⁹ representsa hydroxyl group, R²⁰ represents a hydrogen atom and R²¹ represents ahydroxyl group, with a compound represented by the formula R¹³Z orZ—(CH₂)_(m)—R²², wherein Z represents a halogen atom, in the presence ofa base. Solvents usable herein include, for example, diethyl ether, THF,benzene, toluene, DMF, and DMSO. Bases usable herein include, forexample, sodium hydride, potassium hydride, n-butyllithium, NaCH₂SOCH₃,and tert-BuOK. Preferably, the base and the compound represented by R¹³Zor Z—(CH₂)_(m)—R²² are used in an amount of 1 to 10 equivalents based onthe compound represented by the formula (II). Preferably, the reactionis carried out at −78 to 60° C.

Process (I)

The compound represented by the formula (I), wherein R³ and R⁴ combinewith each other to form oxo, the compound represented by the formula(II), wherein R¹⁸ and R¹⁹ combine with each other to form oxo, and/orR²⁰ and R²¹ combine with each other to form oxo, and the compoundrepresented by the formula (IV), wherein R¹⁸ and R¹⁹ combine with eachother to form oxo, may be prepared respectively by oxidizing thecompound represented by the formula (I), wherein R³ represents ahydrogen atom and R⁴ represents a hydroxyl group, the compoundrepresented by the formula (II), wherein R¹⁸ and R²⁰ represent ahydrogen atom and both R¹⁹ and R²¹ represent a hydroxyl group oralternatively any one of R¹⁹ and R²¹ represents a hydroxyl group withthe other substituent representing a hydrogen atom, and the compoundrepresented by the formula (IV), wherein R¹⁸ represent a hydrogen atomand R¹⁹ represents a hydroxyl group, with an oxidizing agent. Oxidizingagents usable herein include, for example, pyridinium chromate,pyridinium dichromate, manganese dioxide, and DMSO oxidizing reagents,such as DMSO-oxalyl chloride. Solvents usable in this reaction includedichloromethane, chloroform, diethyl ether, and THF. Preferably, theoxidizing agent is used in an amount of 1 to 5 equivalents. The reactionmay be usually carried out at −78 to 40° C.

Process (J)

The compound represented by the formula (I), wherein R³ represents ahydrogen atom and R⁴ represents a hydroxyl group, the compoundrepresented by the formula (II), wherein R¹⁸ and R²⁰ represent ahydrogen atom and both R¹⁹ and R²¹ represents a hydroxyl group oralternatively any one of R¹⁹ and R²¹ represent a hydroxyl group with theother substituent representing a hydrogen atom, and the compoundrepresented by the formula (IV), wherein R¹⁸ represents a hydrogen atomand R¹⁹ represents a hydroxyl group, may be prepared respectively byreducing the compound represented by the formula (I), wherein R³ and R⁴combine with each other to form oxo, the compound represented by theformula (II), wherein R¹⁸ and R¹⁹ combine with each other to form oxo,and/or R²⁰ and R²¹ combine with each other to form oxo, and the compoundrepresented by the formula (IV), wherein R¹⁸ and R¹⁹ combine with eachother to form oxo, with a reducing agent. Reducing agents usable hereininclude, for example, lithium aluminum hydride and sodium boron hydride.In general, the reducing agent may be used in an amount of 1 to 5equivalents. Solvents usable herein include, for example, diethyl ether,THF, benzene, toluene, and dichloromethane. The reaction may be carriedout at −78 to 60° C.

Process (K)

Among the compounds represented by the formula (II), the compoundrepresented by the formula (XXI) may be prepared by the followingprocess.

At the outset, a compound represented by the formula (XXII) may bereacted with a compound represented by the formula WSO₂Cl, wherein Wrepresents alkyl or aryl, in the presence of a base to give the compoundrepresented by the formula (XXIII). Solvents usable herein includebenzene, toluene, dichloromethane, chloroform, diethyl ether, THF, andDMF. Specific examples of compounds represented by the formula WSO₂Clinclude, for example, methanesulfonyl chloride, benzenesulfonylchloride, and p-toluenesulfonyl chloride. Bases usable herein include,for example, triethylamine, pyridine, and 4-dimethylaminopyridine. Ingeneral, the compound represented by the formula WSO₂Cl and the base areused in an amount of 1 to 3 equivalents based on the compoundrepresented by the formula (XXII). The reaction may be usually carriedout at 0 to 60° C.

The compound represented by the formula (XXIII) may be reacted with areducing agent to give the compound represented by the formula (XXI).Solvents usable in this reaction include, for example, diethyl ether,THF, benzene, toluene, and dichloromethane. Reducing agents usableherein include, for example, triethylboronlithium hydride, and may beusually used in an amount of 1 to 5 equivalents. The reaction may becarried out at a temperature of −78 to 60° C.

Process (L)

The compound represented by the formula (IV), wherein R²⁸ represents−C(R⁶)₂OH, may be prepared by reacting a compound represented by theformula (IV), wherein R²⁸ represents —CHO, with a compound representedby the formula (R⁶)_(i)MZ_(j), wherein R⁶ is as defined above, Mrepresents lithium, magnesium, zinc, or aluminum, Z represents a halogenatom, i is an integer of 1 to 3, and j is 0 or 1. Solvents usable inthis reaction include diethyl ether, THF, benzene, toluene, hexane,dimethylformamide (DMF), hexamethylphosphorustriamide, anddichloromethane. Preferably, the compound represented by the formula(R⁶)_(i)MZ_(j) is used in an amount of 1 to 3 equivalents based on thecompound represented by the formula (IV). In general, the reaction maybe carried out at −78 to 20° C.

Process (M)

The compound represented by the formula (IV), wherein R²⁸ represents—CH═CHR⁶, may be prepared by reacting the compound represented by theformula (IV), wherein R²⁸ represents —CHO, with an olefinating reagent.Solvents usable herein include dichloromethane, chloroform, diethylether, THF, DMF, and DMSO. Olefinating reagents usable herein include,for example, Ph₃P═CHR₆, Tebbe reagent, and Nysted reagent. Preferably,the olefinating reagent is used in an amount of 1 to 10 equivalentsbased on the compound represented by the formula (IV). In general, thereaction may be carried out at −78 to 40° C. The addition of a Lewisacid, such as titanium tetrachloride, to this reaction system oftenaccelerates the reaction and, hence, is preferred.

Process (N)

The compound represented by the formula (IV), wherein R²⁸ represents—COR⁶ or —C(R⁶)OH, may be prepared by reacting the compound representedby the formula (II), wherein R²⁸ represents —COOR⁶, with a compoundrepresented by the formula (R⁶)_(i)Mz_(j), wherein R⁶ is as definedabove, M represents lithium, magnesium, zinc, or aluminum, z representsa halogen atom, i is an integer of 1 to 3, and j is 0 or 1. Solventsusable in this reaction include diethyl ether, THF, benzene, toluene,hexane, dimethylformamide (DMF), hexamethylphosphorustriamide, anddichloromethane. Preferably, the compound represented by the formula(R⁶)_(i)MZ_(j) is used in an amount of 1 to 3 equivalents based on thecompound represented by the formula (IV). In general, the reaction maybe carried out at −78 to 20° C.

It would be apparent to a person having ordinary skill in the art thatvarious compounds embraced in the compounds represented by the formulae(I), (II), (III), and (IV) may be prepared by using the above processes(A) to (M) in combination. Further, in the above methods, previouslyprotecting a functional group, which is not involved in the reaction oris unfavorable to be involved in the reaction, is apparent to a personhaving ordinary skill in the art. In this connection, utilization ofprotective groups commonly used in the art are also apparent to a personhaving ordinary skill in the art.

EXAMPLES

The present invention will be described in more detail with reference tothe following examples, though it is not limited to these examples only.

Structures of the following compounds 1 to 74 are summarized in thefollowing table. In the following table, the formula (A) is a structuralformula formed by collectively generalizing the structures respectivelyrepresented by the formulae (I), (II), (III), and (VI).

Compounds 3, 11, 18, and 21 were produced according to a processdescribed in Chem. Pharm. Bull., 36, 153 (1988), and compounds 1 and 7were produced according to processes described in Ber., 70, 2083, 2093(1937), Ber., 71, 790, 1604 (1938), Chem. Pharm. Bull., 31, 664 (1983),and Chem. Pharm. Bull., 31, 674 (1983).

compound R*¹ R*² R*³ R*⁴ R*⁵ R*⁶

1 OH CH₂OH H OH H H ═ 2 OH CH₂OH H OH H H

3 OCMe₂OCH₂ H OH H H ═ 4 OCMe₂OCH₂ H OMe H H ═ 5 OH CH₂OH H OMe H H ═ 6OH CH₂OH H OMe H H

7 OH CH₂OH H OH H OH ═ 8 OH CH₂OH H OH H OH

9 OCMe₂OCH₂ H OCOCH₂OBn H H ═ 10 OH CH₂OH H OCOCH₂OBn H H ═ 11 OH CH₂OTrH OH H H ═ 12 OBn CH₂OTr H OBn H H ═ 13 OBn CH₂OH H OBn H H ═ 14 OBn CHOH OBn H H ═ 15 OBn COCH H OBn H H ═ 16 OBn CONH^(n)Bu H OBn H H ═ 17 OHCONH^(n)Bu H OH H H ═ 18 OH CH₂OH H OCMe₂O H ═ 19 OAc CH₂OAc H OCMe₂O H═ 20 OAc CH₂OAc H OH H OH ═ 21 OMe CH₂OMe H OCMe₂O H ═ 22 OMe CH₂OMe HCH H OH ═ 23 OCH(Ph)OCH₂ H OH H OH ═ 24 OCH(Ph)OCH₂ H OAc H OAc ═ 25OCH(Ph)OCH₂ H OH H OAc ═ 26 OH CH₂OH H OAc H OAc ═ 27 OH CH₂OH H OH HOAc ═ 28 OCH(Ph)OCH₂ H OMe H OMe ═ 29 OCH(Ph)OCH₂ H OH H OMe ═ 30OCH(Ph)OCH₂ H OMe H OH ═ 31 OH CH₂OH H OMe H OMe ═ 32 OH CH₂OH H OH HOMe ═ 33 OH CH₂OH H OMe H OH ═ 34 OCH(Ph)OCH₂ ═O ═O ═ 35 OCH(Ph)OCH₂ ═OH CH ═ 36 OH CH₂OH ═O ═O ═ 37 OH CH₂OH ═O H OH ═ 38 OCH(Ph)OCH₂ OH H OHH ═ 39 OCH(Ph)OCH₂ H OH OH H ═ 40 OCH(Ph)OCH₂ OH H H OH ═ 41 OH CH₂OH HOH OH H ═ 42 OH CH₂OH OH H H OH ═ 43 OCH(Ph)OCH₂ ═O H OAc ═ 44OCH(Ph)OCH₂ H OMs H OAc ═ 45 OCH(Ph)OCH₂ H H H OH ═ 46 OH CH₂CH H H H OH═ 47 OCH(Ph)OCH₂ H H ═O ═ 48 OCH(Ph)OCH₂ H H OH H ═ 49 OH CH₂CH H H OH H═ 50 OCMe₂OCH₂ H OTs H H ═ 51 OCMe₂OCH₂ H ═ H ═ 52 OH CH₂OH H ═ H ═ 53OH CH₂OH H H H H ═ 54 OH CH₂OTr H H H H ═ 55 OCOPh CH₂OTr H H H H ═ 56OCOPh CH₂OH H H H H ═ 57 OCOPh CHO H H H H ═ 58 OH CHO H H H H ═ 59 OHCH(OH)Me H H H H ═ 60 OCOPh COOH H H H H ═ 61 OH COOH H H H H ═ 62 OHCOOMe H H H H ═ 63 OH COMe H H H H ═ 64 OH C(OH)Me₂ H H H H ═ 65 OHCH═CH₂ H H H H ═ 66 OH CH₂OH H H ═O ═ 67 OCMe₂OCH₂ H OCOCH₂CO₂Et H H ═68 OH CH₂OH H OCOCH₂CO₂H H H ═ 69 OCMe₂OCH₂ H O(CH₂)₃CO₂Me H H ═ 70 OHCH₂CH H O(CH₂)₃CO₂Me H H ═ 71 OH CH₂OH H O(CH₂)₃CO₂H H H ═ 72 OCMe₂OCH₂H OCONHPh H H ═ 73 OH CH₂OH H OCONHPh H H ═ 74 OH CH₂OH H OCONH₂ H H ═

Example 1

12α,13α-Epoxyoleanane-3β,22β,24(4β)-triol (compound 2)

Compound 1 (230 mg, 0.5 mmol) was dissolved in 10 ml of dichloromethaneand 3 ml of chloroform, 216 mg of 50-60% m-chloroperoxybenzoic acid wasadded to the solution, and the mixture was stirred at room temperatureovernight. The reaction solution was diluted with dichloromethane,washed with a saturated aqueous sodium bicarbonate solution and thenwith saturated saline, and dried over magnesium sulfate. The inorganicsalt was removed by filtration, and the filtrate was concentrated underreduced pressure to obtain an oil which was then purified by columnchromatography on silica gel (development system, n-hexane:ethylacetate=1:1) to give 193 mg (yield: 81%) of compound 2 as a colorlesssolid.

¹H-NMR (CDCl₃) δ ppm 0.88 (3H, s), 0.90 (3H, s), 0.97 (3H, s), 0.98 (3H,s), 0.99 (3H, s), 1.04 (3H, s), 1.22 (3H, s), 0.74-1.87 (22H, m), 2.36(1H, d, J=4.16 Hz), 2.76 (1H, dd, J=2.50 Hz, 9.16 Hz), 3.05 (1H, s),3.29 (1H, t, J=10.5 Hz), 3.40-3.45 (1H, m), 3.55-3.60 (1H, m), 4.17 (1H,d, J=10.5 Hz)

MS EI (m/z): 474 (M⁺)

Example 2

3β,24(4β)-Isopropylidenedioxy-22β-methoxyolean-12-ene (compound 4)

Compound 3 (300 mg) was dissolved in 5 ml of THF, 130 mg of 55% sodiumhydride was added to the solution, and the mixture was stirred at roomtemperature for 1 hr. Then 2 ml of methyl iodide was added, and themixture was stirred overnight. The reaction solution was diluted withethyl acetate, washed with water, and dried over magnesium sulfate. Theinorganic salt was removed by filtration, and the filtrate wasconcentrated under reduced pressure to obtain a concentrate which wasthen purified by column chromatography on silica gel (developmentsystem, n-hexane:ethyl acetate=10:1) to give 285 mg (yield: 93%) ofcompound 4 as a colorless foam.

¹H-NMR (CDCl₃) δ ppm 0.86 (3H, s), 0.90 (3H, s), 0.99 (3H, s), 1.00 (3H,s), 1.11 (3H, s), 1.15 (3H, s), 1.22 (3H, s), 1.37 (3H, s), 1.44 (3H,s), 0.83-2.10 (21H, m), 2.80-2.83 (1H, m), 3.23 (1H, d, J=11.8 Hz), 3.28(3H, s), 3.44-3.47 (1H, m), 4.06 (1H, d, J=11.8 Hz), 5.23 (1H, t-like)

MS FD (m/z): 512 (M⁺)

Example 3

22β-Methoxyolean-12-ene-3β,24(4β)-diol (compound 5)

Compound 4 (280 mg) was dissolved in THF, 0.66 ml of boron trifluorideethyl ether was added to the solution, and the mixture was stirred atroom temperature for 1 hr. The reaction solution was neutralized with asaturated aqueous sodium hydrogencarbonate solution and extracted withethyl acetate. The extract was dried over magnesium sulfate. Theinorganic salt was removed by filtration, and the filtrate wasconcentrated under reduced pressure to obtain a concentrate which wasthen purified by column chromatography on silica gel (developmentsystem, n-hexane:ethyl acetate=2:1) to give 203 mg (yield: 79%) ofcompound 5 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.85 (3H, s), 0.89 (3H, s), 0.90 (3H, s), 0.94 (3H,s), 1.00 (3H, s), 1.11 (3H, s), 1.25 (3H, s), 0.80-2.10 (21H, m),2.80-2.82 (1H, m), 3.28 (3H, s), 3.33 (1H, d, J=11.1 Hz), 3.42-3.45 (1H,m), 5.22 (1H, t-like)

MS EI (m/z): 472 (M⁺)

Example 4

22β-Methoxy-12,13-epoxyoleanane-3β,24(4β)-diol (compound 6)

Compound 5 (50 mg, 0.1 mmol) was dissolved in 1 ml of dichloromethane,31 mg of 70% m-chloroperoxybenzoic acid was added to the solution, andthe mixture was stirred at room temperature overnight. The reactionsolution was diluted with dichloromethane, washed with a saturatedaqueous sodium bicarbonate solution and then with saturated saline, anddried over magnesium sulfate. The inorganic salt was removed byfiltration, and the filtrate was concentrated under reduced pressure toobtain a solid which was then purified by column chromatography onsilica gel (development system, n-hexane:ethyl acetate=1:1) to give 14.5mg (yield: 28%) of compound 6 as a colorless solid.

¹H-NMR (CDCl₃)δ ppm 0.87 (3H, s), 0.89 (3H, s), 0.96 (3H, s), 0.97 (3H,s), 0.99 (3H, s), 1.04 (3H, s), 1.22 (3H, s), 0.74-1.88 (21H, m), 2.42(1H, br.s), 2.80 (1H, br.s), 2.94 (1H, dd, J=3.33 Hz, 9.71 Hz), 3.04(1H, s), 3.26-3.30 (1H, m), 3.29 (3H, s), 3.40-3.44 (1H, m), 4.17 (1H,d, J=9.71 Hz)

MS EI (m/z):488 (M⁺)

Example 5

12,13-Epoxyoleanane-3β,21β,22β,24(4β)-tetraol (compound 8)

Compound 7 (50 mg, 0.1 mmol) was dissolved in 1 ml of dichloromethaneand 1 ml of chloroform, 32 mg of 70% m-chloroperoxybenzoic acid wasadded to the solution, and the mixture was stirred at 37° C. overnight.The reaction solution was diluted with dichloromethane, washed with asaturated aqueous sodium bicarbonate solution and then with saturatedsaline, and dried over magnesium sulfate. The inorganic salt was removedby filtration, and the filtrate was concentrated under reduced pressureto obtain a solid which was then purified by column chromatography onsilica gel (development system, n-hexane:ethyl acetate=1:1) to give 18mg (yield: 35%) of compound 8 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.91 (3H, S), 1.00 (3H, s), 1.05 (3H,s), 1.13 (3H, s), 1.14 (3H, S), 1.23 (3H, s), 0.75-2.08 (23H, m), 3.03(1H, s), 3.28 (1H, d, J=11.28 Hz), 3.40-3.51 (3H, m), 4.17 (1H, d,J=11.28 Hz)

MS FAB (m/z): 491 (M⁺+1)

Example 6

22β-Benzyloxyacetyloxy-3β,24(4β)-isopropylidenedioxyolean-12-ene(compound 9)

Compound 3 (38 mg) was dissolved in 5 ml of dichloromethane, 15 mg of4-dimethylaminopyridine and 18 μl of benzyloxyacetyl chloride were addedto the solution, and the mixture was stirred at room temperature for 1.5hr. The reaction solution was diluted with dichloromethane, washed withwater, and dried over magnesium sulfate. The inorganic salt was removedby filtration, and the filtrate was concentrated under reduced pressureto obtain a concentrate which was then purified by column chromatographyon silica gel (development system, n-hexane:ethyl acetate=3:1) to give36 mg (yield: 76%) of compound 9 as a colorless foam.

¹H-NMR (CDCl₃) δ ppm 0.81 (3H, s), 0.90 (3H, s), 0.96 (3H, s), 0.98 (3H,s), 1.14 (3H, s), 1.15 (3H, s), 1.22 (3H, s), 1.38 (3H, s), 1.44 (3H,s), 0.87-2.20 (21H, m), 3.23 (1H, d, J=11.65 Hz), 3.46 (1H, dd, J=4.44Hz, 11.44 Hz), 4.03-4.10 (3H, m), 4.64 (2H, d, J=1.94 Hz), 4.78 (1H,t-like), 5.25 (1H, t-like), 7.30-7.39 (5H, m)

MS FAB (m/z): 647 (M⁺+1)

Example 7

22β-Benzyloxyacetyloxyolean-12-ene-3β,24(4β)-diol (compound 10)

Compound 9 (36 mg) was dissolved in 1 ml of dichloromethane and 2 ml ofmethanol, 1 ml of hydrochloric acid was added to the solution, and themixture was stirred at room temperature for 1 hr. The reaction solutionwas diluted with dichloromethane, washed with water, and dried overmagnesium sulfate. The inorganic salt was removed by filtration, and thefiltrate was concentrated under reduced pressure to give 30 mg (yield:88%) of compound 10 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.80 (3H, s), 0.89 (3H, s), 0.90 (3H, s), 0.94 (3H,s), 0.96 (3H, s), 1.14 (3H, s), 1.25 (3H, s), 0.84-2.20 (21H, m), 3.35(1H, d, J=11.1 Hz), 3.42-3.47 (1H, m), 4.10 (2H, dd, J=16.37 Hz, 26.91Hz), 4.20 (1H, d, J =11.1 Hz), 4.64 (2H, d, J=1.67 Hz), 4.78 (1H,t-like), 5.24 (1H, t-like), 7.28-7.38 (5H, m)

MS EI (m/z): 606 (M⁺)

Example 8

3β,22β-Dibenzyloxy-24(4β)-triphenylmethyloxyolean-12-ene (compound 12)

Compound 11 (95 mg) was dissolved in 5 ml of anhydrous DMF, 83 mg of 60%sodium hydride was added to the solution, and the mixture was stirred atroom temperature for 1.5 hr. Thereafter, 75 μl of benzyl bromide wasadded to the reaction mixture, and the mixture was stirred at 40° C. for5 hr. The reaction mixture was diluted with ethyl acetate, washed thricewith water, and dried over magnesium sulfate. The inorganic salt wasremoved by filtration, and the filtrate was concentrated under reducedpressure to obtain an oil which was then purified by columnchromatography on silica gel (development system, n-hexane:ethylacetate=10:1) to give 118 mg (yield: 65%) of compound 12 as a colorlesssolid.

¹H-NMR (CDCl₃) δ ppm 0.33 (3H, s), 0.82 (3H, s), 0.88 (3H, s), 0.92 (3H,s), 1.03 (3H, s), 1.08 (3H, s), 1.34 (3H, s), 0.70-2.15 (21H, m),2.93-2.97 (1H, m), 3.06-3.07 (1H, m), 3.17 (1H, d, J=9.2 Hz), 3.53 (1H,d, J=9.2 Hz), 4.32 (1H, d, J=11.9 Hz), 4.38 (1H, d, J=11.9 Hz), 4.61(1H, d, J=11.9 Hz), 4.63 (1H, d, J=11.9 Hz), 5.17 (1H, t-like),7.19-7.50 (25H, m)

MS FD (m/z): 881 (M⁺+1)

Example 9

3β,22β-Dibenzyloxyolean-12-en-24(4β)-ol (compound 13)

Compound 12 (440 mg) was dissolved in 10 ml of methanol and 2 ml ofacetone. Concentrated hydrochloric acid (0.4 ml) was added to thesolution, and the mixture was refluxed for 30 min. Water was added tothe reaction solution, and the mixture was then neutralized with 1 Nsodium hydroxide and extracted thrice with methylene chloride. Theorganic layer was dried over magnesium sulfate, the inorganic salt wasremoved by filtration, and the filtrate was concentrated under reducedpressure to obtain an oil which was then purified by columnchromatography on silica gel (development system, n-hexane:ethylacetate=10:1) to give 231 mg (yield: 72%) of compound 13 as an oil.

¹H-NMR(CDCl₃) δ ppm 0.88 (3H, s), 0.89 (3H, s), 0.93 (3H, s), 0.94 (3H,s), 1.05 (3H, s), 1.11 (3H, s), 1.21 (3H, s), 0.85-2.18 (22H, m),3.07-3.08 (1H, m), 3.18-3.24 (2H, m), 4.16 (1H, d, J=10.5 Hz), 4.32 (1H,d, J=11.7 Hz), 4.39 (1H, d, J=11.7 Hz), 4.62 (1H, d, J=11.7 Hz), 4.67(1H, d, J=11.7 Hz), 5.22 (1H, t-like), 7.26-7.34 (1OH, m)

MS SIMS (m/z):639 (M⁺+1)

Example 10

3β,22β-Dibenzyloxy-24(4β)-oxolean-12-ene (compound 14)

Oxalyl chloride (0.15 ml) was dissolved in 4 ml of methylene chloride,and the solution was cooled to −78° C. A solution of 0.23 ml of DMSO inmethylene chloride was added to the cooled solution, and the mixture wasstirred for 10 min. A solution of 128 mg of compound 13 in 2 ml ofmethylene chloride was added to the reaction solution thus prepared, andthe mixture was stirred at −78° C. for 15 min. To the reaction solutionwas added 0.7 ml of triethylamine, and the mixture was stirred at −78°C. for 5 min. The temperature of the reaction solution was graduallyraised to 0° C. The reaction solution was diluted with water, extractedwith methylene chloride, washed with saturated sodium hydrogencarbonate,and dried over anhydrous magnesium sulfate. The inorganic salt wasremoved by filtration, the filtrate was concentrated under reducedpressure, and the resultant oil was purified by column chromatography onsilica gel (development system, n-hexane:ethyl acetate=10:1) to give 104mg (yield: 82%) of compound 14 as a colorless foam substance.

¹H-NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.89 (3H, s), 0.93 (3H, s), 0.94 (3H,s), 1.04 (3H, s), 1.10 (3H, s), 1.21 (3H, s), 0.85-2.18 (21H, m), 3.07(1H, dd, J=3.1 Hz, 3.1 Hz), 3.18 (1H, dd, J=5.1 Hz, 5.1 Hz), 4.20, 4.61(1H, each, both d, J=11.7 Hz), 5.23 (1H, t-like), 7.22-7.35 (10H, m),10.07 (1H, s)

MS SIMS (m/z): 637 (M⁺+1)

Example 11

3β,22β-Dibenzyloxyolean-12-en-24(4β)-oic acid (compound 15)

Compound 14 (20 mg) was dissolved in 6 ml of tert-butanol, and 1.5 ml of2-methyl-2-butene was added to the solution. A solution of 250 mg ofsodium chlorite and 250 mg of monosodium phosphate in 2.5 ml of waterwas added to the reaction solution, and the mixture was then stirred atroom temperature overnight. The reaction solution was concentrated underreduced pressure and extracted with ethyl acetate, and the extract wasdried over magnesium sulfate. The inorganic salt was removed byfiltration, and the filtrate was concentrated under reduced pressure toobtain an oil which was then purified by column chromatography on silicagel (development system, n-hexane:ethyl acetate=5:1) to give 6.8 mg(yield: 34%) of compound 15 as a colorless solid.

1H-NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.94 (3H, s), 0.95 (3H, s), 1.02 (3H,s), 1.04 (3H, s), 1.10 (3H, s), 1.40 (3H, s), 0.85-2.19 (21H, m),3.05-3.09 (1H, m), 3.15-3.19 (1H, m), 4.32 (1H, d, J=11.83 Hz), 4.56(1H, d, J=11.83 Hz), 4.61 (1H, d, J=11.83 Hz), 4.85 (1H, d, J=11.83 Hz),5.23 (1H, t-like), 7.23-7.52 (1OH, m).

MS EI (m/z): 652 (M⁺)

Example 12

N-n-Butyl-3β,22β-dibenzyloxyolean-12-en-24(4β)-oic amide (compound 16)

Compound 15 (20 mg) was dissolved in 1 ml of anhydrous DMF. BOP reagent(16 mg) was added to the solution, and the mixture was stirred at roomtemperature for 2 hr. n-Butylamine (0.1 ml) was added to the reactionsolution, and the mixture was stirred at room temperature for 1 hr. Thereaction solution was diluted with ethyl acetate, washed twice withwater, and dried over magnesium sulfate. The inorganic salt was removedby filtration, and the filtrate was concentrated under reduced pressureto obtain a concentrate which was then purified by column chromatographyon silica gel (development system, n-hexane:ethyl acetate=5 : 1) to give16 mg (yield: 73%) of compound 16 as a colorless foam.

¹H-NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.92 (3H, s), 0.93 (3H, s), 1.01 (3H,s), 1.04 (3H, s), 1.10 (3H, s), 1.34 (3H, s), 0.82-2.25 (28H, m),3.08-3.18 (4H, m), 4.32 (1H, d, J=11.65 Hz), 4.46 (1H, d, J=11.65 Hz),4.61 (1H, d, J=11.65 Hz), 4.75 (1H, d, J=11.65 Hz), 5.23 (1H, t-like),7.28-7.37 (1OH, m), 7.50 (1H, t-like)

MS FAB (m/z): 708 (M⁺+1)

Example 13

N-n-Butyl-3β,22β-dihydroxyolean-12-en-24(4β)-oic amide (compound 17)

Compound 16 (13 mg) was dissolved in 1 ml of methanol and 1 ml ofdichloromethane, and 13 mg of 10% Pd—C was added to the solution. Themixture was catalytically reduced at room temperature under atmosphericpressure for 2 hr. The reaction solution was filtered through Celite,and the filtrate was concentrated under reduced pressure to give 10 mg(yield: 100%) of compound 17 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.87 (3H, s), 0.90 (3H, s), 0.92 (3H, s), 1.02 (3H,s), 1.04 (3H, s), 1.12 (3H, S), 1.38 (3H, s), 0.91-2.22 (29H, m),3.10-3.25 (3H,m),3.40-3.45 (1H, m), 3.77 (1H, d, J=8.75 Hz), 5.27 (1H,t-like), 5.97 (1H, t-like)

MS EI (m/z): 527 (M⁺)

Example 14

3β,24(4β)-Diacetoxy-21β,22β-isopropylidenedioxyolean- 12-ene (compound19)

21β,22β-Isopropylidenedioxyolean-12-ene-3β,24(4β)-diol (compound 18) (20mg) was dissolved in 0.5 ml of anhydrous pyridine, 0.5 ml of anhydrousacetic acid was added to the solution, and the mixture was stirred atroom temperature overnight. Ice water was added to the reactionsolution, extracted with ethyl acetate, and dried over magnesiumsulfate. The inorganic salt was removed by filtration, and the filtratewas concentrated under reduced pressure to obtain a concentrate whichwas then purified by column chromatography on silica gel (developmentsystem, n-hexane:ethyl acetate=3:1) to give 19 mg (yield: 80%) ofcompound 19 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.92 (3H, s), 0.98 (9H, s), 1.00 (3H, s), 1.03 (3H,s), 1.11 (3H, s), 1.34 (3H, s), 1.49 (3H, s), 2.04 (3H, s), 2.07 (3H,s), 1.00-2.28 (19H, m), 3.73 (2H, s), 4.14 (1H, d, J=11.5 Hz), 4.37 (1H,d, J=11.5 Hz), 4.57-4.61 (1H, m), 5.27 (1H, t-like)

MS EI (m/z): 598 (M⁺)

Example 15

3β,24(4β)-Diacetoxyolean-12-ene-21β,22β-diol (compound 20)

Compound 19 (18 mg) was dissolved in 0.5 ml of dichloromethane and 1 mlof methanol, 0.2 ml of 1 N hydrochloric acid was added to the solution,and the mixture was stirred at room temperature for 2 hr. The reactionsolution was diluted with dichloromethane, washed with water, and driedover magnesium sulfate. The inorganic salt was removed by filtration,and the filtrate was concentrated under reduced pressure to obtain aconcentrate which was then purified by column chromatography on silicagel (development system, dichloromethane:ethyl acetate=3:1) to give 14mg (yield: 79%) of compound 20 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.96 (3H, s), 0.97 (3H, s), 0.98 (6H, s), 1.02 (3H,s), 1.03 (3H, s), 1.15 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 0.99-2.27(21H, m), 3.41 (1H, t, J=3.6 Hz), 3.51 (1H, 15 dd, J=3.6 Hz, 7.5 Hz),4.14 (1H, d, J=11.7 Hz), 4.37 (1H, d, J=11.7 Hz), 4.56-4.61 (1H, m),5.26 (1H, t-like)

MS FAB (m/z):581 (M+Na⁺)

Example 16

3β,24(4β)-Dimethoxyolean-12-ene-21β,22β-diol(compound 22)

21β,22β-Isopropylidenedioxy-3β,24(4β)-dimethoxyolean- 12-ene (compound21) (15 mg) was dissolved in 1 ml of dichloromethane and 1 ml ofmethanol, 0.2 ml of 1 N hydrochloric acid was added to the solution, andthe mixture was stirred at room temperature for 1.5 hr. The reactionsolution was diluted with dichloromethane, washed with water, and driedover magnesium sulfate. The inorganic salt was removed by filtration,and the filtrate was concentrated under reduced pressure to give 12 mg(yield: 87%) of compound 22 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.97 (6H, s), 0.99 (3H, s), 1.00 (3H, s), 1.02 (3H,s), 1.12 (3H, s), 1.14 (3H, s), 0.73-2.26 (21H, m), 2.72 (1H, dd, J=4.2Hz, 11.9 Hz), 3.27 (3H, s), 3.31 (1H, d, J=9.7 Hz), 3.35 (3H, s), 3.41(1H, t, J=3.6 Hz), 3.51 (1H, dd, J=3.6 Hz, 7.5 Hz), 3.54 (1H, d, J=9.7Hz), 5.27 (1H, t-like)

MS EI (m/z): 502 (M⁺)

Example 17

3β,24(4β)-Benzylidenedioxyolean-12-ene-21β,22β-diol (compound 23)

Soyasapogenol A (compound 7) (1.0 g) was dissolved in 10 ml of anhydrousDMF, and 0.38 ml of benzaldehyde dimethyl acetal and 10 mg ofcamphorsulfonic acid were added to the solution, and the mixture wasstirred at room temperature overnight. The reaction solution was dilutedwith ethyl acetate, washed with a saturated sodium hydrogencarbonatesolution, and dried over magnesium sulfate. The inorganic salt wasremoved by filtration, and the filtrate was concentrated under reducedpressure to obtain a concentrate which was then purified by columnchromatography on silica gel (development system, n-hexane:ethylacetate=2:1) to give 728 mg (yield: 61%) of compound 23 as a colorlesssolid.

¹H-NMR (CDCl₃) δ ppm 0.96 (3H, s), 0.97 (3H, s), 1.00 (3H, s), 1.02 (3H,s), 1.08 (3H, s), 1.17 (3H, s), 1.48 (3H, s), 0.90-2.47 (21H, m), 3.42(1H, br s), 3.51 (1H, br s), 3.62 (1H, d, J=11.0 Hz), 3.64 (1H, dd,J=5.4 Hz, 12.1 Hz), 4.31 (1H, d, J=11.0 Hz), 5.27 (1H, t-like), 5.78(1H, s), 7.32-7.39 (3H, m), 7.49-7.52 (2H, m)

MS FAB (m/z): 585 (M+Na⁺)

Example 18

21β,22β-Diacetoxy-3β,24(4β)-benzylidenedioxyolean-12-ene (compound 24)and

21β-Acetoxy-3β,24(4β)-benzylidenedioxyolean-12-en-22β-ol (compound 25)

Compound 23 (100 mg) was dissolved in 2.5 ml of anhydrous pyridine, 1 mlof anhydrous acetic acid was added to the solution, and the mixture wasstirred at room temperature for 3 hr. Ice water was added to thereaction solution, extracted with ethyl acetate, and dried overmagnesium sulfate. The inorganic salt was removed by filtration, and thefiltrate was concentrated under reduced pressure to obtain a concentratewhich was then purified by column chromatography on silica gel(development system, n-hexane:ethyl acetate=3:1) to give 23 mg (yield:20%) of compound 24 and 69 mg (yield 65%) of compound 25 as colorlesssolids.

¹H-NMR (CDCl₃) δ ppm (compound 24) 0.80 (3H, s), 0.88 (3H, s), 0.97 (3H,s), 1.07 (3H, s), 1.08 (3H, s), 1.18 (3H, s), 1.48 (3H, s), 2.00 (3H,s), 2.07 (3H, s), 0.89-2.47 (19H, m), 3.62 (1H, d, J=11.0 Hz), 3.64 (1H,dd, J=5.1 Hz, 12.1 Hz), 4.30 (1H, d, J=11.0 Hz), 4.90 (2H, s), 5.29 (1H,t-like), 5.78 (1H, s), 7.30-7.39 (3H, m), 7.49-7.52 (2H, m)

MS EI (m/z): 647 (M+H)⁺

¹H-NMR (CDCl₃) δ ppm (compound 25) 0.87 (3H, s), 0.97 (3H, s), 1.00 (3H,s), 1.08 (3H, s), 1.13 (3H, s), 1.18 (3H, s), 1.49 (3H, s), 2.14 (3H,s), 0.90-2.48 (20H, m), 3.46 (1H, d, J=3.1 Hz), 3.62 (1H, d, J=11.3 Hz),3.65 (1H, dd, J=5.9 Hz, 12.8 Hz), 4.31 (1H, d, J=11.3 Hz), 4.94 (1H, d,J=3.1 Hz), 5.28 (1H, t-like), 5.79 (1H, s), 7.28-7.39 (3H, m), 7.49-7.52(2H, m)

MS EI (m/z): 604 (M⁺)

Example 19

21β,22β-Diacetoxyolean-12-ene-3β,24(4β)-diol (compound 26)

Compound 24 (23 mg) was dissolved in 1 ml of methanol and 1 ml ofdichloromethane, and 5 mg of 10% Pd—C was added to the solution. Themixture was catalytically reduced at room temperature under atmosphericpressure for 4 hr. The reaction solution was filtered through Celite,and the filtrate was concentrated under reduced pressure to give 16 mg(yield: 82%) of compound 26 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.79 (3H, s), 0.87 (3H, s), 0.89 (3H, s), 0.94 (3H,s), 1.07 (3H, s), 1.16 (3H, s), 1.25 (3H, s), 0.83-1.98 (18H, m), 2.00(3H, s), 2.06 (3H, s), 2.23-2.28 (1H,m), 2.48 (1H, br s), 2.72 (1H, brs), 3.32-3.38 (1H, m), 3.45 (1H, dd, J=5.4 Hz, 12.1 Hz), 4.20 (1H, d,J=11.1 Hz), 4.89 (2H, s), 5.27 (1H, t-like),

MS EI (m/z): 558 (M⁺)

Example 20

21β-Acetoxyolean-12-ene-3β,22β,24(4β)triol (compound 27)

Compound 25 (20 mg) was dissolved in 1 ml of methanol and 1 ml ofdichloromethane, and 5 mg of 10% Pd—C was added to the solution. Themixture was catalytically reduced at room temperature under atmosphericpressure for 1 hr. The reaction solution was filtered through Celite,and the filtrate was concentrated under reduced pressure to give 13 mg(yield: 79%) of compound 27 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.85 (3H, s), 0.89 (3H, s), 0.96 (6H, s), 1.12 (3H,s), 1.15 (3H, s), 1.25 (3H, s), 0.84-1.98 (19H, m), 2.13 (3H, s),2.28-2.34 (1H, m), 2.43 (1H, br s), 2.71 (1H, br s), 3.32-3.50 (3H, m),4.21 (1H,. d, J=11.1 Hz), 4.93 (1H, d, J=3.3 Hz), 5.26 (1H, t-like),

MS FAB (m/z): 539 (M+Na⁺)

Example 21

3β,24(4β)-Benzylidenedioxy-21β,22β-dimethoxyolean-12-ene (compound 28),

3β,24(4β)-Benzylidenedioxy-22β-methoxyolean-12-en-21 β-ol (compound 29),and

3β,24(4β)-Benzylidenedioxy-21β-methoxyolean-12-en-22β-ol (compound 30)

Compound 23 (20 mg) was dissolved in anhydrous THF, 14 mg of 60% sodiumhydride was added to the solution, and the mixture was stirred at roomtemperature for 1 hr. Thereafter, 32 μl of methyl iodide was added tothe reaction mixture, and the mixture was stirred for 6 hr. Water wasadded to the reaction solution, and the mixture was extracted with ethylacetate. The extract was dried over magnesium sulfate. The inorganicsalt was removed by filtration, and the filtrate was concentrated underreduced pressure to obtain a concentrate which was then purified bycolumn chromatography on silica gel (development system, n-hexane:ethylacetate=3:1) to give 6 mg (yield: 28%) of compound 28, 5 mg (yield: 26%)of compound 29, and 3 mg (yield: 14%) of compound 30 as a colorlesssolid.

¹H-NMR (CDCl₃) δ ppm (compound 28) 0.94 (6H, s), 0.99 (3H, s), 1.03 (3H,s), 1.07 (3H, s), 1.15 (3H, s), 1.48 (3H, s), 0.88-2.47 (19H, m), 3.02(2H, br s), 3.43 (3H, s), 3.46 (3H, s), 3.62 (1H, d, J =11.5 Hz), 3.64(1H, dd, J=5.7 Hz, 12.1 Hz), 4.31 (1H, d, J=11.5 Hz), 5.24 (1H, t-like),5.78 (1H, s), 7.32-7.39 (3H, m), 7.49-7.52 (2H, m)

MS EI (m/z): 590 (M⁺)

¹H-NMR (CDCl₃) δ ppm (compound 29) 0.95 (3H, s), 1.00 (3H, s), 1.01 (3H,s), 1.03 (3H, s), 1.08 (3H, s), 1.16 (3H, s), 1.48 (3H, s), 0.90-2.48(20H, m), 2.99 (1H, d, J=3.3 Hz), 3.40 (3H, s), 3.57 (1H, d, J=3.3 Hz),3.62 (1H, d, J=11.1 Hz), 3.64 (1H, dd, J=5.6 Hz, 12.1 Hz), 4.30 (1H, d,J=11.1 Hz), 5.27 (1H, t-like), 5.79 (1H, s), 7.31-7.38 (3H, m),7.49-7.52 (2H, m)

MS EI (m/z): 576 (M⁺)

¹H-NMR (CDCl₃) δ ppm (compound 30) 0.92 (3H, s), 0.95 (3H, s), 0.96 (3H,s), 0.99 (3H, s), 1.08 (3H, s), 1.15 (3H, s), 1.48 (3H, s), 0.90-2.46(20H, m), 2.91 (1H, d, J=3.9 Hz), 3.44 (1H, d, J=3.9 Hz), 3.47 (3H, s),3.62 (1H, J=10.8 Hz), 3.64 (1H, dd, J=5.4 Hz, 12.1 Hz), 4.30 (1H, d,J=10.8 Hz), 5.24 (1H, t-like), 5.78 (1H, s), 7.31-7.38 (3H, m),7.49-7.52 (2H, m)

MS EI (m/z): 576 (M⁺)

Example 22

21β,22β-Dimethoxyolean-12-ene-3β,24(4β)-diol (compound 31)

Compound 28 (20 mg) was dissolved in 1 ml of methanol and 1 ml ofdichloromethane, and 5 mg of 10% Pd—C was added to the solution. Themixture was catalytically reduced at room temperature under atmosphericpressure for 1 hr. The reaction solution was filtered through Celite,and the filtrate was concentrated under reduced pressure to give 15 mg(yield: 89%) of compound 31 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.93 (6H, s), 0.95 (3H, s), 1.02 (3H,s), 1.13 (3H, s), 1.25 (3H, s), 0.83-1.88 (18H, m), 2.18-2.21 (1H, m),2.41 (1H, br s), 2.74 (1H, br s), 3.01 (2H, s), 3.32-3.50 (2H, m), 3.42(3H, s), 3.45 (3H, s), 4.21 (1H, d, J=11.3 Hz), 5.22 (1H, t-like),

MS EI (m/z): 502 (M⁺)

Example 23

22β-Methoxyolean-12-ene-3β,21β,24(4β)-triol (compound 32)

Compound 29 (13 mg) was dissolved in 1 ml of methanol and 1 ml ofdichloromethane, and 5 mg of 10% Pd—C was added to the solution. Themixture was catalytically reduced at room temperature under atmosphericpressure for 2.5 hr. The reaction solution was filtered through Celite,and the filtrate was concentrated under reduced pressure to give 7 mg(yield: 68%) of compound 32 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.94 (3H, s), 0.96 (3H, s), 0.99 (3H,s), 1.02 (3H, s), 1.14 (3H, s), 1.25 (3H, s), 0.82-1.89 (19H, m),2.25-2.31 (2H, m), 2.41 (1H,br s), 2.73 (1H, br s), 2.98 (1H, d, J=3.3Hz), 3.32-3.37 (1H, m), 3.40 (3H, s), 3.42-3.48 (1H, m), 3.56 (1H, d,J=3.3 Hz), 4.21 (1H, d, J=11.1 Hz), 5.24 (1H, t-like),

MS EI (m/z): 488 (M⁺)

Example 24

21β-Methoxyolean-12-ene-3β,22β,24(4β)-triol (compound 33)

Compound 30 (8 mg) was dissolved in 1 ml of methanol and 1 ml ofdichloromethane, and 5 mg of 10% Pd—C was added to the solution. Themixture was catalytically reduced at room temperature under atmosphericpressure for 1 hr. The reaction solution was filtered through Celite,and the filtrate was concentrated under reduced pressure to give 6 mg(yield: 80%) of compound 33 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.91 (3H, s), 0.94 (3H, s), 0.95 (3H,s), 0.95 (3H, s), 1.13 (3H, s), 1.25 (3H, s), 0.82-2.18 (20H, m), 2.41(1H, br s), 2.73 (1H, br s), 2.90 (1H, d, J=4.0 Hz), 3.32-3.46 (3H, m),3.46 (3H, s), 4.21 (1H, d, J=11.1 Hz), 5.22 (1H, t-like),

MS EI (m/z): 488 (M⁺)

Example 25

3β,24(4β)-Benzylidenedioxy-21,22-dioxolean-12-ene (compound 34) and

3β,24(4β)-Benzylidenedioxy-22-oxolean-12-en-21β-ol (compound 35)

Oxalyl chloride (0.15 ml) was dissolved in 4 ml of dichloromethane, andthe solution was cooled to −78° C. A solution of 0.25 ml of DMSO in 1 mlof dichloromethane was added to the cooled solution, and the mixture wasstirred for 10 min. A solution of 200 mg of compound 23 in 4 ml ofdichloromethane was dropwise added to the reaction solution, and themixture was stirred at −78° C. for 15 min. To the reaction solution wasadded 0.74 ml of triethylamine, and the mixture was stirred at −78° C.for 5 min. The temperature of the reaction solution was gradually raisedto 0° C. Water was added thereto, the mixture was extracted withdichloromethane, and the extract was washed with saturated saline anddried over magnesium sulfate. The inorganic salt was removed byfiltration, the filtrate was concentrated under reduced pressure toobtain a concentrate which was then purified by column chromatography onsilica gel (development system, dichloromethane) to give 76 mg (yield:37%) of compound 34 and 30 mg (yield: 15%) of compound 35 as yellowsolid.

¹H-NMR (CDCl₃) δ ppm (compound 34) 0.98 (3H, s), 1.09 (3H, s), 1.14 (3H,s), 1.15 (3H, s), 1.16 (3H, s), 1.20 (3H, s), 1.49 (3H, s), 0.90-2.63(19H, m), 3.62 (1H, d, J=11.1 Hz), 3.64 (1H, dd, J=5.3 Hz, 11.4 Hz),4.29 (1H, d, J=11.1 Hz), 5.41 (1H, t-like), 5.78 (1H, s), 7.31-7.39 (3H,m), 7.49-7.52 (2H, m)

MS EI (m/z): 558 (M⁺)

¹H-NMR (CDCl₃) δ ppm (compound 35) 0.70 (3H, s), 0.97 (3H, s), 1.06 (3H,s), 1.09 (3H, s), 1.12 (3H, s), 1.27 (3H, s), 1.49 (3H, s), 0.91-2.49(19H, m), 3.60-3.68 (3H, m), 4.19 (1H, d, J=4.2 Hz), 4.30 (1H, d, J=11.1Hz)5.32 (1H, t-like), 5.79 (1H, s), 7.30-7.40 (3H, m), 7.48-7.52 (2H, m)

MS EI (m/z): 560 (M⁺)

Example 26

21,22-Dioxolean-12-ene-3β,24(4β)-diol (compound 36)

Compound 34 (25 mg) was dissolved in 1 ml of dichloromethane and 2 ml ofmethanol, 0.5 ml of 1 N hydrochloric acid was added to the solution, andthe mixture was stirred at room temperature for 4 hr. The reactionsolution was diluted with dichloromethane, washed with water, and driedover magnesium sulfate. The inorganic salt was removed by filtration,and the filtrate was concentrated under reduced pressure to obtain aconcentrate which was then purified by column chromatography on silicagel (development system, n-hexane:ethyl acetate=1:1) to give 12 mg(yield: 59%) of compound 36 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.91 (3H, s), 0.94 (3H, s), 1.13 (3H, s), 1.14 (3H,s), 1.15 (3H, s), 1.18 (3H, s), 1.25 (3H, s), 0.80-2.75(21H, m),3.32-3.39 (1H, m), 3.41-3.49 (1H, m),4.21 (1H, d, J=11.0 Hz), 5.40 (1H,t-like),

MS FAB (m/z): 471 (M+H)⁺

Example 27

22-Oxolean-12-ene-3β,21β,24(4β)-triol (compound 37)

Compound 35 (25 mg) was dissolved in 1 ml of dichloromethane and 2 ml ofmethanol, 0.5 ml of 1 N hydrochloric acid was added to the solution, andthe mixture was stirred at room temperature for 4 hr. The reactionsolution was diluted with dichloromethane, washed with water, and driedover magnesium sulfate. The inorganic salt was removed by filtration,and the filtrate was concentrated under reduced pressure to obtain aconcentrate which was then purified by column chromatography on silicagel (development system, n-hexane:ethyl acetate=1:1) to give 13 mg(yield: 61%) of compound 37 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.69 (3H, s), 0.90 (3H, s), 0.94 (3H, s), 1.05 (3H,s), 1.11 (3H, s), 1.25 (3H, s), 1.26 (3H, s), 0.80-2.73 (21H, m),3.32-3.38 (1H, m), 3.42-3.49 (1H, m), 3.65 (1H, d, J=4.1 Hz), 4.18 (1H,d, J=4.1 Hz), 4.21 (1H, d, J=11.2 Hz), 5.30 (1H, t-like),

MS FAB (m/z): 473 (M+H)⁺

Example 28

3β,24(4β)-Benzylidenedioxyolean-12-ene-21β,22β-diol (compound 23),

3β,24(4β)-Benzylidenedioxyolean-12-ene-21α,22α-diol (compound 38),

3β,24(4β)-Benzylidenedioxyolean-12-ene-21α,22β-diol (compound 39), and

3β,24(4β)-Benzylidenedioxyolean-12-ene-21β,22α,-diol (compound 40)

Lithium aluminum hydride (30 mg) was suspended in 3 ml of anhydrous THF.A solution of compound 34 (193 mg) in 2 ml of anhydrous THF was dropwiseadded to the solution under ice cooling, and the mixture was stirred for2 hr. A saturated sodium sulfate was added to the reaction solution andstirred at room temperature for a while. The insoluble was removed byfiltration, the filtrate was concentrated under reduced pressure toobtain a concentrate which was then purified by column chromatography onsilica gel (development system, n-hexane:THF=3:1) to give 89 mg (yield:46%) of a compound 23/compound 38 mixture, 11 mg (yield: 5%) of compound39, and 8 mg (yield: 4%) of compound 40.

¹H-NMR (CDCl₃) δ ppm (compound 39) 0.85 (3H, s), 0.89 (3H, s), 0.95 (3H,s), 1.08 (6H, s), 1.10 (3H, s), 1.48 (3H, s), 0.85-2.48 (21H, m),3.21-3.44 (2H, m), 3.60-3.68 (2H, m), 4.30 (1H, d, J =11.3 Hz), 5.30(1H, t-like), 5.78 (1H, s), 7.31-7.40 (3H, m), 7.48-7.53 (2H, m)

MS FAB (m/z): 585 (M+Na⁺)

¹H-NMR (CDCl₃) δ ppm (compound 40) 0.91 (3H, s), 0.97 (3H, s), 1.00 (3H,s), 1.01 (3H, s), 1.07 (3H, s), 1.16 (3H, s), 1.48 (3H, s), 0.85-2.48(21H, m), 3.27-3.35 (2H, m), 3.60-3.68 (2H,m), 4.30 (1H, d, J=11.3 Hz),5.25 (1H, t-like), 5.78 (1H, s), 7.30-7.39 (3H, m), 7.48-7.52 (2H, m)

MS FAB (m/z): 585 (M+Na⁺)

Example 29

Olean-12-ene-3β,21α,22β,24(4β)-tetraol (compound 41)

Compound 39 (11 mg) was dissolved in 0.5 ml of dichloromethane and 1 mlof methanol, 0.1 ml of 1 N hydrochloric acid was added to the solution,and the mixture was stirred at room temperature for 4 hr. The reactionsolution was diluted with dichloromethane, washed with water, and driedover magnesium sulfate. The inorganic salt was removed by filtration,and the filtrate was concentrated under reduced pressure to obtain aconcentrate which was then purified by column chromatography on silicagel (development system, n-hexane:ethyl acetate=1:1) to give 3 mg(yield: 34%) of compound 41 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.87 (3H, s), 0.90 (3H, s), 0.91 (3H,s), 1.05 (3H, s), 1.08 (3H, s), 1.23 (3H, s), 0.85-2.27 (23H, m),3.20-3.35 (3H, m), 3.40-3.46 (1H, m), 4.19 (1H, d, J 11.3 Hz), 5.26 (1H,t-like),

MS EI (m/z): 474 (M⁺)

Example 30

Olean-12-ene-3β,21β,22α,24(4β)-tetraol (compound 42)

Compound 40 (9 mg) was dissolved in 0.5 ml of dichloromethane and 1 mlof methanol, 0.1 ml of 1 N hydrochloric acid was added to the solution,and the mixture was stirred at room temperature for 4 hr. The reactionsolution was diluted with dichloromethane, washed with water, and driedover magnesium sulfate. The inorganic salt was removed by filtration,and the filtrate was concentrated under reduced pressure to obtain aconcentrate which was then purified by column chromatography on silicagel (development system, n-hexane:ethyl acetate=1:1) to give 4 mg(yield: 58%) of compound 42 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.90 (3H, s), 0.93 (3H, s), 0.99 (6H,s), 1.14 (3H, s), 1.25 (3H, s), 0.82-2.44 (21H, m), 3.00-3.05 (1H, m),3.10-3.14 (1H, m), 3.22-3.47 (3H,m), 3.42 (1H, dd, J=6.6 Hz, 11.0 Hz),4.20 (1H, d, J=11.0 Hz), 5.23 (1H, t-like),

MS EI (m/z): 474 (M⁺)

Example 31

21β-Acetoxy-3β,24(4β)-benzylidenedioxy-22-oxolean-12-ene (compound 43)

Compound 43 (49 mg, yield: 54%) was prepared from 91 mg of compound 25in the same manner as in Example 18.

¹H-NMR (CDCl₃) δ ppm 0.86 (3H, s), 0.97 (3H, s), 1.03 (3H, s), 1.04 (3H,s), 1.08 (3H, s), 1.27 (3H, s), 1.49 (3H, s), 2.18 (3H, s), 0.90-2.49(19H, m), 3.60-3.68 (2H,m), 4.30 (1H, d, J=11.3 Hz), 5.32 (2H, t-like),5.78 (1H, s), 7.31-7.40 (3H, m), 7.48-7.52 (2H, m)

MS EI (m/z): 602 (M⁺)

Example 32

21β-Acetoxy-3β,24(4β)-benzylidenedioxy-22β-mesyloxyolean-12-ene(compound 44)

Compound 25 (316 mg) was dissolved in 8 ml of anhydrous pyridine, 162 plof methane sulfonyl chloride and a catalytic amount of 4-DMAP were addedto the solution, and the mixture was stirred at room temperatureovernight. Ice water was added to the reaction solution, the mixture wasextracted with ethyl acetate, and the extract was dried over magnesiumsulfate. The inorganic salt was removed by filtration, and the filtratewas concentrated under reduced pressure to obtain a solid which was thenwashed with a mixed solution of n-hexane and ethyl acetate to give 331mg (yield: 93%) of compound 44.

¹H-NMR (CDCl₃) δ ppm 0.91 (3H, s), 0.98 (3H, s), 1.00 (3H, s), 1.08 (3H,s), 1.10 (3H, s), 1.19 (3H, s), 1.49 (3H, s), 2.14 (3H, s), 0.93-2.48(18H, m), 3.08 (3H, s), 3.60-3.68 (2H, m), 3.72-3.78 (1H, m), 4.30 (1H,d, J=11.5 Hz), 4.59 (1H, d, J=3.1 Hz), 4.97 (1H, d, J=3.1 Hz), 5.30 (1H,t-like), 5.78 (1H, s), 7.30-7.39 (3H, m), 7.49-7.52 (2H, m)

MS TSP (m/z): 700 (M+NH₄ ⁺)

Example 33

3β,24(4β)-Benzylidenedioxyolean-12-en-21β-ol (compound 45)

Triethylboronlithium hydride (1.0 M THF solution, 4.6 ml) was added to315 mg of compound 44 under ice cooling, and the mixture was stirred atroom temperature for 15 min. Water was added to the reaction solution,the mixture was extracted with ethyl acetate, and the extract was driedover magnesium sulfate. The inorganic salt was removed by filtration,and the filtrate was concentrated under reduced pressure to obtain aconcentrate which was then purified by column chromatography on silicagel (development system, n-hexane:ethyl acetate=5:1) to give 221 mg(yield: 88%) of compound 45 as a foam substance.

¹H-NMR (CDCl₃) δ ppm 0.85 (3H, s), 0.94 (6H, s), 0.96 (3H, s), 1.08 (3H,s), 1.18 (3H, s), 1.48 (3H, s), 0.90-2.48 (22H, m), 3.47 (1H, br s),3.62 (1H, d, J=11.3 Hz), 3.64 (1H, dd, J=5.1 Hz, 12.1 Hz), 4.30 (1H, d,J=11.3 Hz), 5.24 (1H, t-like), 5.78 (1H, s), 7.30-7.39 (3H, m),7.49-7.52 (2H, m)

MS TSP (m/z): 564 (M+NH₄ ⁺)

Example 34

Olean-12-ene-3β,21β,24(4β)-triol (compound 46)

Compound 46 (18 mg, yield: 46%) as a colorless solid was prepared from46 mg of compound 45 in the same manner as in Example 12.

¹H-NMR (CDCl₃) δ ppm 0.84 (3H, s), 0.89 (3H, s), 0.92 (3H, s), 0.93 (6H,s), 1.16 (3H, s), 1.24 (3H, s), 0.86-2.48 (24H, m), 3.33 (1H, d, J=11.3Hz), 3.39-3.48 (2H, m), 4.20 (1H, d, J=11.3 Hz), 5.22 (1H, t-like),

MS TSP (m/z): 476 (M+NH₄ ⁺)

Example 35

3β,24(4β)-Benzylidenedioxy-21-oxolean-12-ene (compound 47)

Compound 47 (56 mg, yield: 51%) as a colorless solid was prepared from110 mg of compound 45 in the same manner as in Example 25.

¹H-NMR (CDCl₃) δ ppm (compound 34) 0.96 (3H, s), 0.98 (3H, s), 1.02 (3H,s), 1.08 (3H, s), 1.13 (3H, s), 1.21 (3H, s), 1.48 (3H, s), 0.90-2.50(21H, m), 3.62 (1H, d, J=11.3 Hz), 3.64 (1H, dd, J=4.9 Hz, 12.6 Hz),4.30 (1H, d, J=11.3 Hz), 5.34 (1H, t-like), 5.79 (1H, s), 7.30-7.39 (3H,m), 7.49-7.53 (2H, m)

MS FAB (m/z): 567 (M+Na⁺)

Example 36

3β,24(4β)-Benzylidenedioxyolean-12-en-21α-ol (compound 48)

Compound 48 (11 mg, yield: 20%) as a colorless solid was prepared from55 mg of compound 47 in the same manner as in Example 28.

¹H-NMR (CDCl₃) δ ppm (compound 34) 0.86 (3H, s), 0.87 (3H, s), 0.96 (3H,s), 0.97 (3H, s), 1.08 (3H, s), 1.14 (3H, s), 1.48 (3H, s), 0.90-2.48(22H, m), 3.52 (1H, dd, J=4.6 Hz, 12.1 Hz), 3.62 (1H, d, J=11.0 Hz),3.64 (1H, dd, J=5.1 Hz, 11.8 Hz), 4.30 (1H, d, J=11.0 Hz), 5.23 (1H,t-like), 5.78 (1H, s), 7.30-7.39 (3H, m), 7.49-7.53 (2H, m)

MS FAB (m/z): 569 (M+Na⁺)

Example 37

Olean-12-ene-3β,21α,24(4β)-triol (compound 49)

Compound 49 (7 mg, yield: 82%) as a colorless solid was prepared from 11mg of compound 48 in the same manner as in Example 19.

¹H-NMR (CDCl₃+CD₃OD) δ ppm 0.85 (3H, s), 0.86 (3H, s), 0.89 (3H, s),0.92 (6H, s), 0.96 (3H, s), 1.12 (3H, s), 1.23 (3H, s), 0.83-2.21 (21H,m), 3.32 (1H, d, J=11.0 Hz), 3.39-3.45 (1H, m), 3.50 (1H, dd, J=5.6 Hz,11.8 Hz), 4.19 (1H, d, J=11.0 Hz), 5.21 (1H, t-like)

MS TSP (m/z): 459 (M+H)⁺

Example 38

3β,24(4β)-Isopropylidenedioxy-22β-tosyloxyolean-12-ene (compound 50)

Compound 1 (500 mg) was dissolved in pyridine, 287 mg ofp-toluenesulfonyl chloride and a catalytic amount of4-dimethylaminopyridine were added to the solution, and the mixture wasstirred at room temperature overnight. Water was added to the reactionsolution, the mixture was extracted with ethyl acetate, and the extractwas dried over magnesium sulfate. The inorganic salt was removed byfiltration, and the filtrate was concentrated under reduced pressure togive 654 mg (yield 100%) of compound 50 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.76 (3H, s), 0.84 (9H, s), 0.94 (3H, s), 0.96 (3H,s), 1.10 (3H, s), 1.14 (3H, s), 1.21 (3H, s), 1.37 (3H, s), 1.44 (3H,s), 0.78-2.10 (21H, m), 2.45 (3H, s), 3.22 (1H, d, J=11.65 Hz),3.43-3.46 (1H, m), 4.03 (1H, d, J=11.65 Hz), 4.34-4.37 (1H, m), 5.22(1H, t-like)

MS FD (m/z): 652 (M⁺)

Example 39

3β,24(4β)-Isopropylidenedioxyolean-12,21-diene (compound 51)

Triethylboronlithium hydride (1.0 M THF solution, 2 ml) was added to 65mg of compound 50 under ice cooling, and the mixture was stirred at 65°C. for 1 hr. The temperature of the reaction solution was returned toroom temperature. Water was added to the reaction solution, the mixturewas extracted with ethyl acetate, and the extract was dried overmagnesium sulfate. The inorganic salt was removed by filtration, and thefiltrate was concentrated under reduced pressure to obtain a solid whichwas then purified by column chromatography on silica gel (developmentsystem, n-hexane:ethyl acetate=10:1) to give 38 mg (yield: 79%) ofcompound 51 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.88 (3H, s), 0.96 (9H, s), 0.98 (3H, s), 0.99 (3H,s), 1.12 (3H, s), 1.17 (3H, s), 1.22 (3H, s), 1.38 (3H, s), 1.44 (3H,s), 0.90-2.13 (19H, m), 3.23 (1H, d, J=11.54 Hz), 3.45-3.48 (1H, m),4.05 (1H, d, J=11.54 Hz), 5.20-5.32 (3H, m)

MS EI (m/z): 480 (M⁺)

Example 40

Olean-12,21-diene-3β,24(4β)-diol (compound 52)

Compound 51 (48 mg) was dissolved in 1 ml of methanol and 1 ml ofdichloromethane, 0.5 ml of 1 N hydrochloric acid was added to thesolution, and the mixture was stirred for 1 hr. The reaction solutionwas diluted with dichloromethane, washed with water, and dried overmagnesium sulfate. The inorganic salt was removed by filtration, and thefiltrate was concentrated under reduced pressure to give 36 mg (yield:82%) of compound 52 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.87 (3H, s), 0.90 (3H, s), 0.94 (3H, s), 0.95 (3H,s), 0.98 (3H, s), 1.11 (3H, s), 1.25 (3H, s), 0.84-2.13 (19H, m), 2.36(1H, d, J=4.10 Hz), 2.68 (1H, d, J =6.67 Hz), 3.32-3.37 (1H, m),3.43-3.48 (1H, m), 4.21 (1H, d, J=11.28 Hz), 5.20-5.30 (3H, m)

MS EI (m/z): 440 (M⁺)

Example 41

Olean-12-ene-3β,24(4β)-diol (compound 53)

Compound 51 (30 mg) was dissolved in 2 ml of methanol and 1 ml ofdichloromethane, and 5 mg of 20% Pd(OH)₂—C was added to the solution.The mixture was catalytically reduced under atmospheric pressureovernight. The reaction solution was filtered, and the filtrate wasconcentrated under reduced pressure to give 26 mg (yield: 93%) ofcompound 53 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.82 (3H, s), 0.87 (6H, s), 0.89 (3H, s), 0.93 (3H,s), 1.13 (3H, s), 1.25 (3H, s), 1.25 (3H, s), 0.78-2.03 (23H, m), 2.37(1H, d, J=4.16 Hz), 2.71 (1H, dd, J =2.50 Hz, 8.88 Hz), 3.32-3.37 (1H,m), 3.42-3.48 (1H, m), 4.21 (1H, d, J=10.88 Hz), 5.18 (1H, t-like)

MS EI (m/z): 442 (M⁺)

Example 42

3β-Benzoyloxyolean-12-en-24(4β)-ol (compound 56)

Compound 53 (1.00 g, 2.26 mmol) was dissolved in 10 ml of pyridine.Trityl chloride (881 mg, 3.16 mmol) was added to the solution, and themixture was refluxed for 5 hr. The solvent was removed by distillation,water was added to the residue, the mixture was extracted with ethylacetate, and the extract was dried over sodium sulfate. The inorganicsalt was removed by filtration, and the filtrate was concentrated underreduced pressure to obtain 1.5 g of compound 54 (crude product). Thecompound 54 (crude product, 1.5 g) was dissolved in 20 ml ofdichloromethane, 690 mg of 4-DMAP and 476.5 mg of benzoyl chloride wereadded to the solution, and the mixture was stirred for 2 hr. Thereaction solution was diluted with dichloromethane, washed with water,and dried over sodium sulfate. The inorganic salt was removed byfiltration, and the filtrate was concentrated under reduced pressure togive 1.7 g of compound 55 (crude product). The compound 55 (crudeproduct, 1.7 g) was dissolved in 20 ml of methanol and 50 ml of acetone.Concentrated hydrochloric acid (0.5 ml) was added to the solution, andthe mixture was stirred at 70° C. for 2 hr. The reaction solution wasthen neutralized with 1 N sodium hydroxide, and the solvent was removedby distillation. Water was added to the residue, the mixture wasextracted with ethyl acetate, and the extract was dried over sodiumsulfate. The inorganic salt was removed by filtration, and the filtratewas concentrated under reduced pressure to obtain a crude product whichwas then purified by column chromatography on silica gel (developmentsystem, n-hexane:ethyl acetate=10:1) to give 818 mg (yield: 66%) ofcompound 56 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.84 (3H, s), 0.87 (3H, s), 0.88 (3H, s), 0.98 (3H,s), 1.14 (3H, s), 1.15 (3H, s), 1.60 (3H, s), 0.80-2.10 (24H, m), 3.59(1H, t, J=10.7 Hz), 4.26 (1H, dd, J=11.7 Hz, 2.6 Hz), 4.92 (1H, dd,J=8.6 Hz, 7.6 Hz), 5.19 (1H, t, J=3.6 Hz), 7.43-7.60 (3H, m), 7.96-8.00(2H, m).

FABMS (m/z): 569 (M⁺+Na)

Example 43

3β-Benzoyloxy-24(4β)-oxolean-12-ene (compound 57)

Compound 56 (1.50 mg) was dissolved in 5 ml of dichloromethane, 71.1 mgof pyridinium chlorochromate was added to the solution, and the mixturewas stirred for 1 hr. One hr after the initiation of stirring, 71.1 mgof pyridinium chlorochromate was added to the reaction solution, and themixture was further stirred for 1 hr. Silica gel was added to thereaction solution, followed by filtration. The filtrate was concentratedunder reduced pressure to obtain a crude product which was then purifiedby column chromatography on silica gel (development system,n-hexane:ethyl acetate=20:1) to give 142 mg (yield:95%) of compound 57as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.88 (3H, s), 0.91 (3H, s), 0.96 (3H,s), 1.16 (3H, s), 1.17 (3H, s), 1.58 (3H, s), 0.80-2.20 (23H, m), 4.93(1H, dd, J=11.4 Hz, 5.9 Hz), 5.20 (1H, t, J=3.5 Hz), 7.41-7.59 (3H, m),7.97-8.00 (2H, m), 10.23 (1H, s).

FABMS (m/z): 545 (M⁺+1)

Example 44

24(4β)-Oxolean-12-en-3β-ol (compound 58)

Compound 57 (121 mg, 0.222 mmol) was dissolved in 3 ml of methanol and 4ml of THF, 0.5 ml of 1 N sodium hydroxide was added to the solution, andthe mixture was stirred for 3 hr. The reaction solution was neutralizedwith 1 N hydrochloric acid, and the solvent was removed by distillation.Water was added to the residue, the mixture was extracted with ethylacetate, and the extract was dried over sodium sulfate. The inorganicsalt was removed by filtration, and the filtrate was concentrated underreduced pressure to obtain a crude product which was then purified bycolumn chromatography on silica gel (development system, n-hexane:ethylacetate=12:1) to give 75.4 mg (yield: 77%) of compound 58 as a colorlesssolid.

¹H-NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.87 (9H, s), 0.99 (3H, s), 1.14 (3H,s), 1.29 (3H, s), 0.80-2.10 (23H, m), 3.10-3.25 (2H, m), 5.19 (1H, t,J=3.6 Hz), 9.77 (1H, d, J=2.3 Hz).

FABMS (m/z): 441 (M++l)

Example 45

24(4β)-Methylolean-12-ene-3β,24(4β)-diol (compound 59)

Compound 58 (50.0 mg, 0.114 mmol) was dissolved in 2 ml of THF, and thesolution was cooled to −78°. An ether solution of MeLi (0.42 ml, 1.08mmol/ml) was added to the solution at the same temperature. Thetemperature of the mixture was gradually raised to 0° C. over a periodof 30 min, followed by stirring at 0° C. for additional 10 min. Waterwas added to the reaction solution, the mixture was extracted with ethylacetate, and the extract was dried over sodium sulfate. The inorganicsalt was removed by filtration, and the filtrate was concentrated underreduced pressure to obtain a crude product which was then purified bypreparative TLC (development system, n-hexane:THF=2.2:1) to give 39.0 mg(yield: 75%) of compound 59 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.87 (6H, s), 0.96 (3H, s), 0.97 (3H,s), 1.12 (3H, s), 1.17 (3H, s), 1.23 (3H, d, J=6.3 Hz), 0.80-2.10 (25H,m), 3.42 (1H, dd, J=12.1 Hz, 3.8 Hz), 4.57 (1H, q, J=6.3 Hz), 5.19 (1H,t, J=3.6 Hz).

FABMS (m/z): 479 (M⁺+Na)

Example 46

3β-Benzyloxyolean-12-en-24(4β)-oic acid (compound 60)

Compound 57 (300 mg) was dissolved in 15 ml of tert-butanol, and 2.93 mlof 2-methyl-2-butene was added to the solution. A solution of 250 mg ofsodium chlorite and 430 mg of monosodium phosphate in 2.0 ml of waterwas added to the mixture, and the mixture was then stirred at roomtemperature overnight. The reaction solution was concentrated underreduced pressure, the concentrate was extracted with ethyl acetate, andthe extract was dried over sodium sulfate. The inorganic salt wasremoved by filtration, and the filtrate was concentrated under reducedpressure to obtain an oil which was then purified by columnchromatography on silica gel (development system, n-hexane:ethylacetate=4:1) to give 261 mg (yield: 85%) of compound 60 as a colorlesssolid.

¹H-NMR (CDCl₃) δ ppm 0.84 (3H, s), 0.87 (3H, s), 0.88 (3H, s), 1.00 (3H,s), 1.01 (3H, s), 1.16 (3H, s), 1.37 (3H, s), 0.80-2.60 (23H, m), 4.81(1H, dd, J 12.3 Hz, 4.3 Hz), 5.21 (1H, t, J=3.4 Hz), 7.40-7.58 (3H, m),8.05-8.08 (2H, m),

FABMS (m/z): 583 (M⁺+Na)

Example 47

Methyl{olean-12-en-3β-ol-24(4β)-ate} (compound 62)

Compound 60 (251 mg) was dissolved in 1 ml of methanol and 6 ml of THF,1 ml of 4 N sodium hydroxide was added to the solution, and the mixturewas stirred at room temperature overnight. It was then adjusted to pH 3by the addition of 1 N hydrochloric acid, and the solvent was removed bydistillation. Water was added to the residue, the mixture was extractedwith ethyl acetate, and the extract was dried over sodium sulfate. Theinorganic salt was removed by filtration, and the filtrate wasconcentrated under reduced pressure to obtain a concentrate which wasdissolved in 6 ml of methanol and 6 ml of THF. An excessive amount of asolution of trimethylsilyldiazomethane in hexane was added to thesolution, and the mixture was stirred at room temperature for 1 min. Thereaction solution was concentrated under reduced pressure to obtain acrude product which was then purified by column chromatography on silicagel (development system, n-hexane:ethyl acetate=15:1) to give 136 mg(yield: 65%) of compound 62 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.79 (3H, s), 0.83 (3H, s), 0.87 (3H, s), 0.98 (3H,s), 1.13 (3H, s), 1.41 (3H, s), 1.58 (3H, s), 0.80-2.10 (23H, m), 3.09(1H, td, J=12.0 Hz, 4.5 Hz), 3.34-3.38 (1H, m), 3.68 (3H, s), 5.19 (1H,t, J=3.5 Hz).

FABMS (m/z): 493 (M⁺+Na)

Example 48

24(4β)-Methyl-24(4β)oxolean-12-en-3β-ol (compound 63) and

24(4β),24(4β)-Dimethylolean-12-ene-3β,24(4β)-diol (compound 64)

Compound 62 (30.0 mg) was dissolved in 2 ml of THF, and the solution wascooled to −78° C. An ether solution of MeLi (0.71 ml, 1.08 mmol/ml) wasadded to the solution at the same temperature. The temperature of themixture was gradually raised to room temperature over a period of 30m,n. and the mixture was stirred at room temperature for 4 hr. Water wasadded to the reaction solution, the mixture was extracted with ethylacetate, and the extract was dried over sodium sulfate. The inorganicsalt was removed by filtration, and the filtrate was concentrated underreduced pressure to obtain a crude product which was then purified bypreparative TLC (development system, n-hexane:THF=6:1) to give 16.7 mg(yield: 58%) of compound 63 and 3.4 mg (yield: 11%) of compound 64 as acolorless solid.

¹H-NMR (CDCl₃) δ ppm (compound 63) 0.81 (3H, s), 0.83 (3H, s), 0.87 (3H,s), 1.01 (3H, s), 1.14 (3H, s), 1.39 (3H, s), 1.59 (3H, s), 2.18 (3H,s), 0.80-2.20 (23H, m), 3.05 (1H, td, J=11.9 Hz, 4.1 Hz), 3.18-3.22 (1H,m), 5.20 (1H, t, J=3.6 Hz).

FABMS (m/z): 454 (M⁺+1)

¹H-NMR (CDCl₃) δ ppm (compound 64) 0.83 (3H, s), 0.87 (6H, s), 1.02 (3H,s), 1.12 (3H, s), 1.19 (3H, s), 1.22 (3H, s), 1.41 (3H, s), 1.42 (3H,s), 0.80-2.40 (25H, m), 3.37-3.43 (1H, m), 5.21 (1H, t, J=3.6 Hz).

FABMS (m/z): 493 (M⁺+Na)

Example 49

22-Methyleneolean-12-en-3-ol (compound 65)

Compound 58 (25 mg) was dissolved in 1 ml of THF, 0.57 ml of 0.5 mmol/mlsolution of the Tebbe reagent in toluene was added to the solution at 0,and the mixture was stirred at 0t for 30 min and then at roomtemperature overnight. Diethyl ether and 1 N NaoH were added to thereaction solution, followed by filtration. The filtrate was concentratedunder reduced pressure. Water was added to the concentrate, the mixturewas extracted with ethyl acetate, and the extract was then dried oversodium sulfate. The inorganic salt was removed by filtration, and thefiltrate was concentrated under reduced pressure to obtain a crudeproduct which was then purified by preparative TLC (development system,n-hexane:THF=5 1) to give 17.9 mg (yield: 72%) of compound 65 as acolorless solid.

¹H-NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.87 (6H, s), 0.93 (3H, s), 0.94 (3H,s), 1.14 (3H, s), 1.18 (3H, s), 0.80-2.10 (24H, m), 3.20-3.35 (1H, m),5.09 (1H, dd, J=17.6 Hz, 1.7 Hz), 5.17-5.24 (2H, m), 6.06 (1H, dd,J=17.6 Hz, 11.2 Hz).

FABMS (m/z): (M⁺+Na)

Example 50

21-Oxolean-12-en-3β,24(4β)-diol (compound 66)

Compound 66 (6 mg, yield: 100%) was prepared from 7 mg of compound 47 inthe same manner as in Example 19.

¹H-NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.93 (3H, s), 0.94 (3H, s), 1.00 (6H,s), 1.11 (3H, s), 1.20 (3H, s), 1.25 (3H, s), 0.83-2.50 (23H, m), 3.34(1H, d, J=11.0 Hz), 3.45 (1H, dd, J =3.8 Hz, 11.0 Hz), 4.21 (1H, d,J=11.0 Hz), 5.32 (1H, t-like)

MS TSP (m/z):474 (M+NH₄ ⁺)

Example 51

22-Ethylmalonyloxy-3β,24 (4β)-isopropylidenedioxyolean-12-ene (compound67)

Compound 3 (100 mg) was dissolved in 3 ml of dichloromethane, 37 mg of4-dimethylaminopyridine and 38 pl of ethylmalonyl chloride were added tothe solution, and the mixture was stirred at room temperature for 30min. A saturated sodium hydrogencarbonate solution was added to thereaction solution, and the reaction solution was extracted twice withdichloromethane. The organic layer was washed with saturated saline anddried over magnesium sulfate. The inorganic salt was removed byfiltration, and the filtrate was concentrated under reduced pressure toobtain a concentrate which was then purified by column chromatography onsilica gel (development system, n-hexane:ethyl acetate=5:1) to give 85mg (yield: 67%) of compound 67 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.83 (3H, s), 0.90 (3H, s), 0.98 (3H, s), 0.99 (3H,s), 1.15 (3H, s), 1.16 (3H, s), 1.22 (3H, s), 1.28 (3H, t, J=7.2 Hz),1.38 (3H, s), 1.44 (3H, s), 0.86-2.21 (21H, m), 3.23 (1H, d, J=11.5 Hz),3.35 (2H, s), 3.46 (1H, dd, J=4.6 Hz, 9.5 Hz), 4.05 (1H, d, J=11.5 Hz),4.19 (2H, q, J=7.2 Hz), 4.73 (1H, t-like), 5.32 (1H, t-like)

MS TSP (m/z): 635 (M+Na⁺)

Example 52

22β-Malonyloxyolean-12-ene-3β,24(4β)-diol (compound 68)

Compound 67 (73 mg) was dissolved in 5 ml of ethanol and 1 ml ofdichloromethane, 0.8 ml of 1 N sodium hydroxide was added to thesolution, and the mixture was stirred at room temperature for 1 hr. Thereaction solution was acidified with 1 N hydrochloric acid and extractedwith dichloromethane. The extract was concentrated under reducedpressure. The concentrate was dissolved in 2 ml of methanol and 1 ml ofdichloromethane, 0.5 ml of 1 N hydrochloric acid was added to themixture, and the mixture was stirred at room temperature for 30 min.Water was added to the reaction solution, the mixture was extracted withdichloromethane, and the extract was then dried over magnesium sulfate.The inorganic salt was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give 54 mg (yield: 83%) ofcompound 68 as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ ppm 0.81 (3H, s), 0.87 (3H, s), 0.88 (3H, s),0.91 (3H, s), 0.96 (3H, s), 1.12 (3H, s), 1.22 (3H, s), 0.84-2.20 (21H,m), 3.28-3.44 (2H, m), 3.33 (2H, s), 4.18 (1H, d, J=11.3 Hz), 4.71 (1H,t-like), 5.22 (1H, t-like)

MS FAB (m/z): 567 (M+Na⁺)

Example 53

3β,24(4β)-Isopropylidenedioxy-22β-methoxycarbonylpropoxyolean-12-ene(compound 69)

Compound 3 (50 mg) was dissolved in 1 ml of anhydrous DMF, 20 mg of 60%sodium hydride was added to the solution, and the mixture was stirred atroom temperature for 2.5 hr. Thereafter, 87 μl of trimethyl4-bromoorthobutyrate was added to the reaction solution, and the mixturewas stirred at 50r overnight. Ethyl acetate was added to the reactionsolution, and the mixture was washed twice with water, and dried overmagnesium sulfate. The inorganic salt was removed by filtration, and thefiltrate was concentrated under reduced pressure to obtain a concentratewhich was then purified by column chromatography on silica gel(development system, n-hexane:ethyl acetate=5:1) to give 15 mg (yield:24%) of compound 69 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.86 (3H, s), 0.88 (3H, s), 0.99 (3H, s), 1.00 (3H,s), 1.12 (3H, s), 1.16 (3H, s), 1.22 (3H, s), 1.38 (3H, s), 1.44 (3H,s), 0.82-2.13 (23H, m), 2.43 (2H, t, J=7.2 Hz), 2.86-2.89 (1H, m),3.16-3.22 (1H, m), 3.23 (1H, d, J =11.5 Hz), 3.46 (1H, dd, J=4.6 Hz, 9.5Hz), 3.52-3.58 (1H, m), 3.67 (3H, s), 4.05 (1H, d, J=11.5 Hz), 5.23 (1H,t-like)

MS TSP (m/z): 599 (M+H)⁺

Example 54

22β-Methoxycarbonylpropoxyolean-12-ene-3β,24(4β)-diol (compound 70)

Compound 69 (15 mg) was dissolved in 1 ml of methanol and 0.5 ml ofdichloromethane, 0.2 ml of 1 N hydrochloric acid was added to thesolution, and the mixture was stirred at room temperature for 15 min.The reaction solution was extracted with dichloromethane, and theextract was dried over magnesium sulfate. The inorganic salt was removedby filtration, and the filtrate was concentrated under reduced pressureto give 13 mg (yield: 94%) of compound 70 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.86 (3H, s), 0.87 (3H, s), 0.89 (3H, s), 0.94 (3H,s), 1.00 (3H, s), 1.11 (3H, s), 1.25 (3H, s), 0.83-2.13 (25H, m), 2.42(2H, t, J=7.2 Hz), 2.86-2.88 (1H, m), 3.16-3.22 (1H, m), 3.32-3.38 (1H,m), 3.42-3.48 (1H, m), 3.52-3.58 (1H, m), 3.67 (3H, s), 4.21 (1H, d,J=11.0 Hz), 5.21 (1H, t-like)

MS TSP (m/z): 576 (M+NH₄ ⁺)

Example 55

Olean-12-ene-3β,24(4β)-diol-22β-o-propanecarboxylic acid (compound 71)

Compound 70 (13 mg) was dissolved in 2 ml of methanol and 1 ml ofdichloromethane, 0.8 ml of 1 N sodium hydroxide was added to thesolution, and the mixture was stirred at room temperature for 10 hr. Thereaction solution was acidified with 1 N hydrochloric acid and extractedwith dichloromethane, and the extract was dried over magnesium sulfate.The inorganic salt was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give 10 mg (yield: 83%) ofcompound 71 as a colorless solid.

¹H-NMR (CDCl₃+CD₃OD) δ ppm 0.86 (3H, s), 0.88 (3H, s), 0.89 (3H, s),0.94 (3H, s), 1.00 (3H, s), 1.11 (3H, s), 1.24 (3H, s), 0.82-2.12 (23H,m), 2.43 (2H, t, J=7.2 Hz), 2.88-2.91 (1H, m), 3.20-3.26 (1H, m), 3.33(1H, d, J=11.0 Hz), 3.39-3.44 (1H, m), 3.53-3.60 (1H, m), 4.20 (1H, m),5.22 (1H, t-like)

MS TSP (m/z): 543 (M−H)⁻

Example 56

3β,24(4β) -Isopropylidenedioxy-22β-anilinecarbonyloxyolean-12-ene(compound 72)

Compound 3 (30.0 mg) was dissolved in 2 ml of pyridine, 14 mg of phenylisocyanate was added to the solution, and the mixture was refluxed for 1hr. Water was added to the reaction solution, the mixture was extractedwith ethyl acetate, and the extract was dried over sodium sulfate. Theinorganic salt was removed by filtration, and the filtrate wasconcentrated under reduced pressure to obtain a solid which was thenpurified by preparative TLC (development system, n-hexane:THF=7:1) togive 23.0 mg (yield: 62%) of compound 72 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.89 (3H, s), 0.92 (3H, s), 1.00 (3H, s), 1.02 (3H,s), 1.16 (6H, s), 1.23 (3H, s), 1.38 (3H, s), 1.44 (3H, s), 0.80-2.30(21H, m), 3.23 (1H, d, J=11.6 Hz), 3.46 (1H, dd, J=9.3, 4.1 Hz), 4.05(1H, d, J=11.6 Hz), 4.65 (1H, t, J=3.8 Hz), 5.27 (1H, t-like), 6.50 (1H,s), 7.05 (1H, t, J=7.2 Hz), 7.28-7.42 (4H, m).

FABMS (m/z): 640 (M+Na)⁺

Example 57

22β-Anilinocarbonyloxyolean-12-ene-3β,24(4β)-diol (compound 73)

Compound 72 (20.0 mg) was dissolved in 1 ml of methanol, 0.1 ml of 1 NHCl was added to the solution, and the mixture was stirred at roomtemperature for 5 min. The solvent was removed by distillation, asaturated NaHCO₃ solution was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was dried over sodium sulfate.The inorganic salt was removed by filtration, and the filtrate wasconcentrated under reduced pressure to obtain a solid which was thenpurified by preparative TLC (development system, n-hexane:THF=2.5:1) togive 16.2 mg (yield: 87%) of compound 73 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.88 (3H, s), 0.90 (3H, s), 0.92 (3H, s), 0.95 (3H,s), 1.02 (3H, s), 1.15 (3H, s), 1.25 (3H, s), 0.80-2.70 (23H, m),3.31-3.49 (2H, m), 4.21 (1H, dd, J=11.4, 2.0 Hz), 4.65 (1H, t, J=4.1Hz), 5.26 (1H, t, J=3.2 Hz), 6.49 (1H, s), 7.05 (1H, t, J=7.4 Hz),7.27-7.43 (4H, m).

FABMS (m/z): 600 (M+Na)⁺

Example 58

22β-Aminocarbonyloxyolean-12-ene-3β,24(4β)-diol (compound 74)

Compound 3 (5.6 mg) was dissolved in 0.2 ml of pyridine, 4.2 mg oftrichloroacetyl isocyanate was added to the solution, and the mixturewas stirred at room temperature for 1 hr. The reaction solution wasconcentrated under reduced pressure to obtain a solid. Methanol (0.5 ml)and 6.2 mg of potassium carbonate were added to the solid, and themixture was stirred at room temperature for 10 min. The solvent wasremoved by distillation, water was added to the residue, and the mixturewas extracted with ethyl acetate. The extract was dried over sodiumsulfate. The inorganic salt was removed by filtration, and the filtratewas concentrated under reduced pressure to obtain a solid which was thenpurified by preparative TLC (development system, n-hexane:AcOEt=1:1.5)to give 2.5 mg (yield: 44%) of compound 74 as a colorless solid.

¹H-NMR (CDCl₃) δ ppm 0.84 (3H, s), 0.89 (3H, s), 0.90 (3H, s), 0.95 (3H,s), 1.00 (3H, s), 1.14 (3H, s), 1.25 (3H, s), 0.80-2.80 (23H, m),3.32-3.48 (2H, m), 4.21 (1H, d, J 11.0 Hz), 4.48-4.56 (3H, m), 5.24 (1H,t, J=3.5 Hz)

FABMS (m/z): 524 (M+Na)⁺

Preparation Example 1

Tablets

The compound of the present invention was granulated by the wet process,magnesium stearate was added thereto, and the mixture was compressed toprepare tablets. Each tablet had the following composition.

Compound 2 200 mg Lactose 50 mg Carboxymethyl starch sodium 20 mgHydroxypropylmethyl cellulose 5 mg Magnesium stearate 3 mg Total 278 mg

Preparation Example 2

Suppositories

Weilapzole H-15 was heated at 60° C., the compound 2 was added to anddispersed in the resultant melt, and the dispersion was filled intosuppository containers. The suppository containers filled with thedispersion were cooled to room temperature to prepare suppositories.Each suppository had the following composition.

Compound 2 200 mg Weilapzole H-15 1000 mg Total 1200 mg

Test Example 1

Effect in hepatocytotoxicity inhibitory model (in vitro)

A test compound was added to a concentration of 0.1 to 10 μg/ml to HepG2 cells in the presence of aflatoxin B₁ (10⁻⁵ M), and the cells werethen incubated in a CO₂ incubator at 37° C. for 48 hr. After thecompletion of the incubation, the cells were dyed with trypan blue, andthe dye incorporation capacity thereof was measured with Monocellater(manufactured by Olympus Optical Co., Ltd.). The hepatocytotoxicityinhibitory activity (%) was calculated according to the followingequation. In the equation, the value of the control group is theabsorbance (%) in the presence of aflatoxin B₁ alone, and the value ofthe treated group is the absorbance (%) in the copresence of aflatoxinB₁ and the test compound.

As a result, the hepatocytotoxicity inhibitory activity of the compounds2, 6, 10, 17, 20, 22, 26, 27, 32, 33, 36, 37, 46, 49, 66, and 73 was notless than 5%. $\begin{matrix}{Hepatocytotoxicity} \\{{inhibitory}\quad {activity}\quad (\%)}\end{matrix} = {\frac{\begin{matrix}{{value}\quad {of}\quad {control}} \\{group}\end{matrix} - \begin{matrix}{{value}\quad {of}\quad {treated}} \\{group}\end{matrix}}{100 - {{value}\quad {of}\quad {control}\quad {group}}} \times 100}$

Test Example 2

Effect in concanavalin A (Con A) hepatitis model

Con A dissolved in physiological saline was intravenously administeredat a dose of 20 mg/kg to BALB/c male mice (8 weeks in age) having a bodyweight of 21 to 25 g to induce hepatitis. A test compound (compound 7)was suspended in a mixed solution (control vehicle) composed of 25%dimethylsufoxide, 25% polyethylene glycol 400, and 0.25% carboxymethylcellulose, and the suspension was subcutaneously administered 2 hr and14 hr before the administration of Con A at three levels of dose, i.e.,0.2 mg/mouse, 1.0 mg/mouse, and 2.0 mg/mouse. A control vehicle alonewas administered to a group of control mice. Twenty four hr after theadministration of Con A, the mice were sacrificed under ether anesthesiato assay the alanine aminotransferase (ALT) activity, in plasma, as anindex of hepatopathy.

The results were as shown in FIG. 1. Specifically, the ALT activity was2068±518 (u/1) for the group of mice which had not been treated with thetest compound (control group), whereas the ALT activity was lowered tothe same level as that for the group of mice which had not been treatedwith Con A (that is, normal value), that is, 55±16 (u/l) for the groupof mice which had been treated with the compound 7 at a dose of 1.0mg/mouse and the group of mice which had been treated with the compound7 at a dose of 2.0 mg/mouse.

What is claimed is:
 1. A triterpene derivative represented by thefollowing formula (III) or a salt thereof:

wherein R¹ represents a hydroxyl group, lower alkoxy, or loweralkanoyloxy; R² represents —CH₂OR⁵, wherein R⁵ represents a hydrogenatom, arylmethyl, lower alkyl, or lower alkanoyl, Y represents a singlebond to form a double bond in the ring with Y bonded thereto, and R²⁷represents —O—(CH₂)_(m)—R²², wherein R²² represents amino, —NH—COOR²³,wherein R²³ represents arylmethyl or lower alkyl, a hydroxyl group,arylmethoxy, or —COOR²⁴, wherein R²⁴ represents a hydrogen atom, loweralkyl, or arylmethyl, and m is an integer of 1 to 4,—OCOCH(R²⁵)(CH₂)_(n)—R²², wherein R²² is as defined above, R²⁵represents a hydrogen atom, lower alkyl, aralkyl, or aryl, and n is aninteger of 0 to 3, —OCON(R²⁹)R³⁰, wherein R²⁹ and R³⁰, which may be thesame or different, represent a hydrogen atom, lower alkyl, loweralkanoyl, aryl, or aralkyl, —OCO—(CH₂)_(n)—R¹⁶, wherein R¹⁶ represents ahydroxyl group, arylmethoxy, lower alkoxy, or lower alkanoyloxy, or—OCOCH═CH—COOR⁶, wherein R⁶ represents a hydrogen atom or lower alkyl.2. The triterpene derivative according to claim 1, wherein R²⁷represents —OCO—(CH₂)_(n)—R¹⁶.
 3. The triterpene derivative according toclaim 1, wherein R²⁷ represents —O—(CH₂)_(m)—R²².
 4. The triterpenederivative according to claim 1, wherein R²⁷ represents—OCOCH(R²⁵)(CH₂)_(n)—R²² or —OCOCH═CH—COOR⁶.
 5. The triterpenederivative according to claim 1, wherein R²⁷ represents —OCON(R²⁹)R³⁰.6. A pharmaceutical composition for treating a hepatic disorder,comprising the compound according to any one of claims 1 to 5 as anactive ingredient.
 7. A triterpene derivative represented by thefollowing formula (IV) or a salt thereof:

wherein R¹ represents a hydroxyl group, arylmethoyloxy, lower alkoxy, orlower alkanoyloxy; Y represents a single bond to form a double bond inthe ring with Y bonded thereto, R¹⁸ and R¹⁹, which may be the same ordifferent, represent a hydrogen atom, a hydroxyl group, or —OR¹³,wherein R¹³ represents lower alkyl, lower cycloalkyl, aralkyl, loweralkanoyl, arylcarbonyl, aralkylcarbonyl, lower alkenyl, loweralkenylcarbonyl, or aryl-lower alkenylcarbonyl, R²⁸ represents—CON(R²⁹)R³⁰, wherein R²⁹ and R³⁰, which may be the same or different,represent a hydrogen atom, lower alkyl, lower alkanoyl, aryl, oraralkyl, —C(R⁶)₂OH, wherein R⁶ represents a hydrogen atom or loweralkyl, —COR^(6a), wherein R^(6a) represents lower alkyl, or —CH═CHR⁶,wherein R⁶ is as defined above, provided that when R²⁸ represents—C(R⁶)₂OH, R¹⁸ and R¹⁹ do not represent a hydrogen atom at the sametime.
 8. A pharmaceutical composition for treating a hepatic disorder,comprising the compound according to claim 7 as an active ingredient.